System and method for nested neurostimulation

ABSTRACT

A method and system are provided to deliver nested stimulation to brain tissue of interest. The method and system set first parameters that define a carrier waveform. The method and system set second parameters that define a high frequency waveform, wherein at least one of the carrier waveform and high frequency waveform are defined to correspond to physiologic neural oscillations associated with the brain tissue of interest. The method and system operates a pulse generator to generate a nested stimulation waveform that combines the carrier waveform and high frequency waveform. The nested stimulation waveform has a plurality of pulse bursts. The method and system deliver the nested stimulation waveform through one or more electrodes to the brain tissue of interest.

RELATED APPLICATIONS

The present application is a continuation of U.S. patent applicationSer. No. 16/133,521 filed Sep. 17, 2018 which is a continuation of Ser.No. 14/851,540 filed Sep. 11, 2015 which claims priority to U.S. PatentApplication Ser. No. 62/049,086 filed Sep. 11, 2014, titled “NESTEDNEUROSTIMULATION”, all of which are incorporated herein by reference intheir entirety.

BACKGROUND OF THE INVENTION

Embodiments of the present disclosure generally relate toneurostimulation (NS), and more particularly to delivering nestedneurostimulation.

NS systems are devices that generate electrical pulses and deliver thepulses to nervous tissue to treat a variety of disorders. For example,spinal cord stimulation has been used to treat chronic and intractablepain. Another example is deep brain stimulation, which has been used totreat movement disorders such as Parkinson's disease and affectivedisorders such as depression. SCS therapy, delivered via epidurallyimplanted electrodes, is a widely used treatment for chronic intractableneuropathic pain of different origins. Traditional tonic therapy evokesparesthesia covering painful areas of a patient. During SCS therapycalibration, the paresthesia is identified and localized to the painfulareas by the patient in connection with determining correct electrodeplacement.

Recently, new stimulation configurations such as burst stimulation andhigh frequency stimulation, have been developed, in which closely spacedhigh frequency pulses are delivered. In general, conventionalneurostimulation systems seek to manage pain and other pathologic orphysiologic disorders through stimulation of select nerve fibers thatcarry pain related signals. However, nerve fibers and brain tissue carryother types of signals, not simply pain related signals.

A need remains for methods and systems that deliver therapies thatstimulate brain tissue, in order to override or after pathologicalneural oscillations to treat a neurological condition.

SUMMARY

In accordance with embodiments herein a method is provided to delivernested stimulation to nerve tissue of interest. The nerve tissue ofinterest may represent various types of nerve tissue, such as braintissue, spinal cord tissue, dorsal root ganglion tissue and the like.The method comprises setting first parameters that define a carrierwaveform. The method further provides setting second parameters thatdefine a high frequency waveform, wherein at least one of the carrierwaveform and high frequency waveform are defined to correspond tophysiologic neural oscillations associated with the nerve tissue ofinterest. The method further operates a pulse generator to generate anested stimulation waveform that combines the carrier waveform and highfrequency waveform. The nested stimulation waveform has a plurality ofpulse bursts. The method delivers the nested stimulation waveformthrough one or more electrodes to the nerve tissue of interest.

Optionally, the high frequency waveform corresponds to high-frequencyphysiologic neural oscillations associated with the nerve tissue ofinterest. The pulse bursts includes pulses may have a frequencycorresponding to the high frequency neural oscillations. The carrierwaveform may correspond to low-frequency physiologic neural oscillationsassociated with the nerve tissue of interest. The pulse bursts areseparated from one another with a burst to burst period that correspondsto a frequency of the low-frequency neural oscillations. The first andsecond parameters define at least one of an amplitude, burst to burstfrequency, pulse frequency, pulse width, burst length and burst periodfor the plurality of pulse bursts. The method further comprisescombining the carrier and high-frequency waveforms utilizing one of thefollowing types of cross frequency coupling: power to power; phase topower; phase to phase; phase to frequency; power to frequency andfrequency to frequency.

Optionally, the carrier and high-frequency waveforms are combinedthrough phase to power cross frequency coupling, in which the phase ofthe carrier waveform modulates the power of the high-frequency waveform.The first parameters may be set to define the carrier waveform tocorrespond to the theta wave frequency band, while the second parametersmay be set to define the high-frequency waveform to correspond to thegamma wave frequency band. The method further comprises managing thenested stimulation waveform modulating the neural oscillations in thegamma wave frequency band in connection with at least one of sensory,motor, and cognitive events. The method manages the nested stimulationwaveform in connection with an event of interest through cross frequencycoupling between theta and gamma waves associated with the nerve tissueof interest.

The nerve tissue of interest may comprise distributed neural moduleslocated in separate regions of the brain. Optionally, the method furthercomprises managing the nested stimulation waveform in connection withcross frequency coupling between neural oscillations associated with thedistributed neural modules that exhibit long-distance communication overneural oscillations within at least one of delta, theta and alpha wavefrequency bands. Optionally, the method measures intrinsic neuraloscillations, determines whether the nested stimulation waveform isachieving entrainment of the intrinsic neural oscillations, and adjustsat least one of the first and second parameters to maintain entrainmentof the intrinsic neural oscillations.

In accordance with embodiments herein a system is provided to delivernested stimulation to nerve tissue of interest. The system comprises alead having an array of stimulation electrodes. The lead is configuredto be implanted at a target position proximate to nerve tissue ofinterest. An implantable medical device (IMD) is coupled to the lead.The IMD includes a processor and memory storing programmableinstructions. The processor executes the programmable instructions toset first parameters that define a carrier waveform. Further theprocessor sets second parameters that define a high frequency waveform,wherein at least one of the carrier waveform and high frequency waveformare defined to correspond to physiologic neural oscillations associatedwith the nerve tissue of interest. The processor further operates apulse generator to generate a nested stimulation waveform that combinesthe carrier waveform and high frequency waveform, the nested stimulationwaveform having a plurality of pulse bursts; and delivers the nestedstimulation waveform through one or more electrodes to the nerve tissueof interest.

Optionally, the high frequency waveform corresponds to high-frequencyphysiologic neural oscillations associated with the nerve tissue ofinterest, and the pulse bursts including pulses having a frequencycorresponding to the high frequency physiologic neural oscillations. Thecarrier waveform corresponds to low-frequency physiologic neuraloscillations associated with the nerve tissue of interest. The pulsebursts are separated from one another with a burst to burst period thatcorresponds to a frequency of the low-frequency neural oscillations. Thefirst and second parameters define at least one of an amplitude, burstto burst frequency, pulse frequency, pulse width, burst length and burstperiod for the plurality of pulse bursts.

Optionally, the processor combines the carrier and high-frequencywaveforms utilizing one of the following types of cross frequencycoupling: power to power; phase to power phase to phase; phase tofrequency; power to frequency and frequency to frequency. The processormay combine the carrier and high-frequency waveforms through phase topower cross frequency coupling, in which the phase of the carrierwaveform modulates the power of the high-frequency waveform.

The brain tissue of interest may comprise distributed neural moduleslocated in separate regions of the brain. The processor manages thenested stimulation waveform in connection with cross frequency coupledbetween neural oscillations associated with the distributed neuralmodules that exhibit long-distance communication over neuraloscillations within at least one of delta, theta and alpha wavefrequency bands. Optionally, the lead includes sensing electrodes. Theprocessor measures intrinsic neural oscillations through the sensingelectrodes, determines whether the nested stimulation waveform isachieving entrainment of the intrinsic neural oscillations, and adjustsat least one of the first and second parameters to maintain entrainmentof the intrinsic neural oscillations.

BRIEF DESCRIPTION OF THE DRAWINGS

FIG. 1A illustrates an example neurological stimulation (NS) system forelectrically stimulating a predetermined site area to treat one or moreneurological disorders or conditions in accordance with embodimentsherein.

FIG. 1B illustrates an example neurological stimulation (NS) systems forelectrically stimulating a predetermined site area to treat one or moreneurological disorders or conditions in accordance with embodimentsherein.

FIG. 1C depicts an NS system that delivers nested therapies inaccordance with embodiments herein.

FIG. 2A illustrates example stimulation leads that may be used forelectrically stimulating the predetermined site to treat one or moreneurological disorders or conditions in accordance with embodimentsherein.

FIG. 2B illustrates example stimulation leads that may be used forelectrically stimulating the predetermined site to treat one or moreneurological disorders or conditions in accordance with embodimentsherein.

FIG. 2C illustrates example stimulation leads that may be used forelectrically stimulating the predetermined site to treat one or moreneurological disorders or conditions in accordance with embodimentsherein.

FIG. 2D illustrates example stimulation leads that may be used forelectrically stimulating the predetermined site to treat one or moreneurological disorders or conditions in accordance with embodimentsherein.

FIG. 2E illustrates example stimulation leads that may be used forelectrically stimulating the predetermined site to treat one or moreneurological disorders or conditions in accordance with embodimentsherein.

FIG. 2F illustrates example stimulation leads that may be used forelectrically stimulating the predetermined site to treat one or moreneurological disorders or conditions in accordance with embodimentsherein.

FIG. 2G illustrates example stimulation leads that may be used forelectrically stimulating the predetermined site to treat one or moreneurological disorders or conditions in accordance with embodimentsherein.

FIG. 2H illustrates example stimulation leads that may be used forelectrically stimulating the predetermined site to treat one or moreneurological disorders or conditions in accordance with embodimentsherein.

FIG. 2I illustrates example stimulation leads that may be used forelectrically stimulating the predetermined site to treat one or moreneurological disorders or conditions in accordance with embodimentsherein.

FIG. 3 illustrates an example of the various brainwave frequency bandsin accordance with embodiments herein.

FIG. 4 illustrates examples of cross frequency coupling variations thatmay be used in accordance with embodiments herein.

FIG. 5 illustrates a model of a portion of the brain with interestdirected to neural modules in accordance with embodiments herein.

FIG. 6 illustrates a model reflecting the memory functionality of abrain in accordance with embodiments herein.

FIG. 7A illustrates models proposed, in the 2007 Jensen paper, regardingcomputational roles for cross-frequency interactions between theta andgamma oscillations by means of phase coding in accordance withembodiments herein.

FIG. 7B illustrates models proposed, in the 2007 Jensen paper, regardingcomputational roles for cross-frequency interactions between theta andgamma oscillations by means of phase coding in accordance withembodiments herein.

FIG. 8A illustrates an example of a nested stimulation waveform that maybe delivered in connection with nested therapies to brain tissue (orbrain tissue) of interest in accordance with embodiments herein.

FIG. 8B illustrates an example of a nested stimulation waveform that maybe delivered in connection with nested therapies to brain tissue (orbrain tissue) of interest in accordance with embodiments herein.

FIG. 8C illustrates an alternative example of a nested stimulationwaveform that may be delivered in connection with nested therapies tobrain tissue (or brain tissue) of interest in accordance withembodiments herein.

FIG. 9 illustrates alternative nested stimulation waveforms that may beutilized in accordance with embodiments herein.

FIG. 10 illustrates a process for managing delivery of nestedstimulation waveforms to tissue of interest in accordance withembodiments herein.

FIG. 11 illustrates a process for collecting and analyzing neuraloscillations in connection with identifying desired nested stimulationwaveforms in accordance with embodiments herein.

FIG. 12 illustrates a process for defining a nested stimulation waveformbased on neural oscillations in accordance with embodiments herein.

DETAILED DESCRIPTION

While multiple embodiments are described, still other embodiments of thedescribed subject matter will become apparent to those skilled in theart from the following detailed description and drawings, which show anddescribe illustrative embodiments of disclosed inventive subject matter.As will be realized, the inventive subject matter is capable ofmodifications in various aspects, all without departing from the spiritand scope of the described subject matter. Accordingly, the drawings anddetailed description are to be regarded as illustrative in nature andnot restrictive.

I. Definitions

Unless defined otherwise, technical and scientific terms used hereinhave the same meaning as commonly understood by one of ordinary skill inthe art to which this invention belongs. For purposes of thedescription, the following terms are defined below. Further, additionalterms are used herein that shall have definitions consistent with thedefinitions set forth in U.S. Pat. No. 8,401,655, which is expresslyincorporated herein by reference in its entirety.

As used herein, the use of the word “a” or “an” when used in conjunctionwith the term “comprising” in the claims and/or the specification maymean “one,” but it is also consistent with the meaning of “one or more,”“at least one,” and “one or more than one.” Still further, the terms“having”, “including”, “containing” and “comprising” are interchangeableand one of skill in the art is cognizant that these terms are open endedterms.

As used herein, the term “burst firing” or “burst mode” refers to anaction potential that is a burst of high frequency spikes/pulses (e.g.400-1000 Hz) (Beurrier et al., 1999). Burst firing acts in a non-linearfashion with a summation effect of each spike/pulse. One skilled in theart is also aware that burst firing can also be referred to as phasicfiring, rhythmic firing (Lee 2001), pulse train firing, oscillatoryfiring and spike train firing, all of these terms used herein areinterchangeable.

As used herein, the term “tonic firing” or “tonic mode” refers to anaction potential that occurs in a linear fashion.

As used herein, the term “burst” refers to a period in a spike trainthat has a much higher discharge rate than surrounding periods in thespike train (N. Urbain et al., 2002). Thus, burst can refer to aplurality of groups of spike pulses. A burst is a train of actionpotentials that, possibly, occurs during a ‘plateau’ or ‘active phase’,followed by a period of relative quiescence called the ‘silent phase’(Nunemaker, Cellscience Reviews Vol 2 No. 1, 2005.) Thus, a burstcomprises spikes having an inter-spike interval in which the spikes areseparated by 0.5 milliseconds to about 100 milliseconds. Those of skillin the art realize that the inter-spike interval can be longer orshorter. Yet further, those of skill in the art also realize that thespike rate within the burst does not necessarily occur at a fixed rate;this rate can be variable.

The terms “pulse” and “spike” are used interchangeably to refer to anaction potential. Yet further, a “burst spike” refers to a spike that ispreceded or followed by another spike within a short time interval(Matveev, 2000), in otherwords, there is an inter-spike interval, inwhich this interval is generally about 100 ms but can be shorter orlonger, for example 0.5 milliseconds.

Embodiments herein are described for methods and systems that seek tomodify brain wave activity in connection with treating variouspathologic disorders.

Different firing modes or frequencies of neural oscillations occur inthe brain and/or other neuronal tissue, for example tonic firing andburst firing (irregular or regular burst firing). The thalamus utilizesboth types of firing modes. The two thalami (bilateral pairedstructures) are the gateways to the cerebral cortex and, thus, toconsciousness. The thalamic nuclei specialize in several differentsignaling functions: transmitting signals from sensory input to thecortex; transmitting signals from cortical motor centers to effectors;transmitting control signals that select which input and output will bepermitted to pass to and from the cortex and how the signals will besequenced (thalamic reticular nuclei (TRN)); and modulating (controllingintensity) and synchronizing (grouping) the signals (Intralaminar Nuclei(ILN)).

All thalamic relay neurons pass through the TRN, which opens and closestheir “gates” going to the cortex, (McAlonan and Brown, 2002). One modethat TRN neurons use to transmit these relays is burst firing mode. Thismode is useful for activating a small population of neurons in thecortex for a short period. In contrast, the continuous (tonic) firingmode permits a thalamic neuron to transmit a steady stream of signals tothe cortex. The tonic firing pattern triggers looping activation in thecortical circuits that receive the signals. Evoking looping, or“recurrent” activation in the cortex requires a steady neural input.

In general, humans display different types of neural oscillations or“brain waves” across the cortex. The different types of neuraloscillation or bain wave activity can be decomposed into distinctfrequency bands that are associated with particular physiologic andpathologic characteristics. FIG. 3 illustrates an example of the variousbrainwave frequency bands which include infraslow waves 302 (less than 1Hz); delta waves 304 (1-4 Hz); theta waves 306 (4-8 Hz); alpha waves 308(8-12 Hz), beta waves 310 (12-30 Hz), gamma waves 312 (greater than 30Hz), and sigma waves (not shown) (greater than 500 Hz). Individualbrainwave frequency bands and combinations of brainwave frequency bandsare associated with various mental, physical and emotionalcharacteristics. It should be recognized that the cutoff frequencies forthe frequency bands for the various types of brain waves areapproximations. Instead, the cutoff frequencies for each frequency bandmay be slightly higher or lower than the examples provided herein.

Neural oscillations from various combinations of the brainwave frequencybands have been shown to exhibit coupling with one another, wherein oneor more characteristics of one type of brainwave effect (or are affectedby) one or more characteristics of another type of brainwave. Ingeneral, the coupling phenomenon is referred to as cross frequencycoupling, various aspects of which are described in the papersreferenced herein. Combinations of frequency bands couple with oneanother to different degrees, while the coupling of various types ofbrainwaves may occur in connection with physiologic behavior orpathologic behavior. For example, theta and gamma frequency coupling hasbeen identified at the hippocampalcortical in connection withphysiologic behavior. delta-gamma and delta-beta frequency coupling havebeen identified in connection with pathologic limbic dysrhythmia. Asanother example, alpha-gamma frequency coupling has been identified atthe pulvinar region in connection with pathologic thalamocorticaldysrhythmia.

In general, higher frequency brainwave neural oscillations are at leastloosely coupled to one or more lower frequency brainwave neuraloscillations. For example, the phase of delta waves has been found tomodulate the amplitude of theta waves. Further, theta waves have beenfound to modulate the amplitude of gamma waves.

Optionally, more than one level of coupling or nesting may be achievedsuch as through a nesting hierarchy in which one or more high frequencyranges nest with one or more low frequency ranges. For example,combinations of the following frequency ranges may couple/nest with oneanother infraslow (0.01-1 Hz), delta (1-3 Hz), theta (4-7 Hz), alpha(8-12 Hz), beta (13-30 Hz), gamma (31-100 Hz) to ultrafast waves (>100Hz-1200 Hz). When a nesting hierarchy occurs, an intermediate or higherfrequency range may itself become a carrier wave for an even higherfrequency wave. For example, delta waves may represent a carrier forbeta waves, while the beta waves represent a carrier for gamma orultrafast waves.

FIG. 4 illustrates examples of cross frequency coupling variations thatmay be used in accordance with embodiments herein. There are differentprinciples of cross-frequency interactions. FIG. 4 illustrates variousexample brain waves 402-408. As one example, a carrier wave 402 maycorrespond to a slow oscillatory signal in the theta band (e.g. 8 Hz).Although the frequency remains fairly constant, the power (as denoted byline 440) of the signal fluctuates over time. The gamma oscillations caninteract in different ways with other signal oscillations.

The brain waves 403-408 illustrate examples of how the carrier andsecondary waves 402 and 403 may be combined. For example, the wave 403as illustrated has been frequency coupled to the carrier wave 402 in apower to power matter such that the amplitude of the secondary wave 402reduces (as denoted at intermediate region 410) as the amplitude of thecarrier wave 402 reduces (as denoted in region 412). The amplitude ofthe secondary wave 403 is at a maximum in the regions 414 and 416corresponding to the maximum amplitudes of the carrier wave 402. Thefluctuations in power of the faster gamma oscillations are correlatedwith power changes in the lower frequency band. This interaction isindependent of the phases of the signals.

The brainwave 404 represents the carrier and secondary waves 402 and403, as frequency coupled in a phase to phase manner. Given that thecarrier and secondary waves 402 and 403 are aligned in phase with oneanother, the brainwave 404 exhibits a relatively even signal with littlenotable phase shift. Phase-locking occurs between oscillations atdifferent frequencies. In each slow cycle, there are four faster cyclesand their phase relationship remains fixed.

The brainwave 405 represents the carrier and secondary waves 402 and403, as frequency coupled in a phase to power manner. For example, theamplitude of the resulting brainwave 405 is modulated based on the phaseof the carrier wave 402. Accordingly, the brainwave 405 exhibits amaximum in amplitude in regions 418 which correspond to the positive 90°phase shift point (at reference numerals 420) in the carrier wave 402.The brainwave 405 exhibits a minimum amplitude in regions 422 whichcorrespond to the negative 90° phase shift point (at reference numerals424) in the carrier wave 402. Hence, in the example of brainwave 405,the amplitude of the higher frequency brainwave is modulated/determinedby the phase of the lower frequency carrier wave.

The brain waves 406-408 reflect the carrier and secondary waves 402 and403 when coupled in different manners, namely phase to frequency(brainwave 406), power to frequency (brainwave 407) and frequency tofrequency (brainwave 408). It is recognized that the brain wavesillustrated in FIG. 4 represent non-limiting examples and may be shapedin the numerous other manners. The different types of cross-frequencyinteraction are not mutually exclusive. For instance, the phase of thetaoscillations might modulate both frequency and power of the gammaoscillations.

As explained herein, nested stimulation may be applied such that two,three or more frequency bands are coupled to one another to achievevarious results. As noted above, the lower band represents a carrierwave with higher frequency bands nested on the lower carrier wave. Thehigher frequency bands carry content to be utilized by the targetedneural modules. For example, the high-frequency content may besuperimposed into the phase of the lower carrier wave, such as inconnection with external information transmission. Alternatively, thehigh-frequency content may be added while maintaining phasesynchronization. Optionally, the high-frequency content may be addedthrough amplitude or frequency modulation to the lower carrier wave. Itis recognized that the high-frequency content may be added in othermanners as well, based on the particular neural region of interest anddesired effect that is being sought.

The brain organization is shaped by an economic trade-off betweenminimizing costs and allowing efficiency in connection with adaptivestructural and functional topological connectivity patterns. Forexample, a low-cost, but low efficiency, organization would represent aregular lattice type topology. At an opposite end of the spectrum, arandom topology would be highly efficient, but be more economicallycostly.

In general, the brain represents a modular scale free hierarchicalnetwork. The network comprises various regions or modules that areassociated with different characteristics and activities. In accordancewith embodiments herein, electrodes may be positioned proximate tovarious brain tissue of interest and generate nested stimulationwaveforms. For example, the auditory cortex is the part of the temporallobe that processes auditory information. The somatosensory cortexrepresents the main sensory receptive area for the sense of touch. Thethalamus is a structure in the middle of the brain located between thecerebral cortex and the midbrain that correlates various processes suchas consciousness, sleep and sensory interpretation. The cerebellum playsan important role in balance, motor control, but is also involved insome cognitive functions such as attention, language, emotionalfunctions (such as regulating fear and pleasure responses) and in theprocessing of procedural memories. The cerebrum (or forebrain) isdivided by a large groove, known as the longitudinal fissure, into twodistinct hemispheres. The left and right hemispheres are linked by alarge bundle of nerve fibers called the corpus callosum, and also byother smaller connections called commissures. Most of the elements ofinterest of the cerebrum, are split into symmetrical pairs in the leftand right hemispheres. The right hemisphere generally controls the leftside of the body, and vice versa, although popular notions that logic,creativity, etc., are restricted to the left or right hemispheres arelargely simplistic and unfounded. The cerebrum is covered by a sheet ofneural tissue known as the cerebral cortex (or neocortex), whichenvelops other brain organs such as the thalamus (which evolved to helprelay information from the brain stem and spinal cord to the cerebralcortex) and the hypothalamus and pituitary gland (which control visceralfunctions, body temperature and behavioral responses such as feeding,drinking, sexual response, aggression and pleasure).

A large portion of the brain's neurons are located in the cerebralcortex, mainly in the “grey matter”, which makes up the surface regionsof the cerebral cortex, while the inner “white matter” consists mainlyof myelinated axons. The cerebral cortex plays a role in memory,attention, perceptual awareness, thought, language and consciousness. Itis divided into four main regions or lobes, which cover bothhemispheres: the frontal lobe (involved in conscious thought and highermental functions such as decision-making, particularly in that part ofthe frontal lobe known as the prefrontal cortex, and plays an importantpart in processing short-term memories and retaining longer termmemories which are not task-based); the parietal lobe (involved inintegrating sensory information from the various senses, and in themanipulation of objects in determining spatial sense and navigation);the temporal lobe (involved with the senses of smell and sound, theprocessing of semantics in both speech and vision, including theprocessing of complex stimuli like faces and scenes, and plays a keyrole in the formation of long-term memory); and the occipital lobe(mainly involved with the sense of sight).

The medial temporal lobe (the inner part of the temporal lobe, near thedivide between the left and right hemispheres) in particular is thoughtto be involved in declarative and episodic memory. Deep inside themedial temporal lobe is the region of the brain known as the limbicsystem, which includes the hippocampus, the amygdala, the cingulategyrus, the thalamus, the hypothalamus, the epithalamus, the mammillarybody and other organs, many of which are of particular relevance to theprocessing of memory. The hippocampus, for example, is essential formemory function, particularly the transference from short- to long-termmemory and control of spatial memory and behavior. The hippocampus isone of the few areas of the brain capable actually growing new neurons,although this ability is impaired by stress-related glucocorticoids. Theamygdala also performs a primary role in the processing and memory ofemotional reactions and social and sexual behavior, as well asregulating the sense of smell. Nested therapy may be delivered to thebrain tissue regions to treat various pathologies.

It has been proposed that the number of gamma cycles per theta cycledetermines the span of the working memory. It has been further proposedthat the rate of item retrieval is consistent with the period of thegamma cycle (as measured in the Steinberg paradigm (Jensen 2007). It hasbeen proposed the cross frequency interaction between gamma and thetaoscillations are consistent with, and predictive of, expected workingmemory operations. Nested therapy may be utilized to treat disorders inthe working memory.

FIG. 5 illustrates a model of a portion of the brain with interestdirected to neural modules 502 and 504. Local activity within modules502 and 504 generally exhibits high frequency brain waves/oscillations(as generally denoted by the links 506 and 508). For example, thehigh-frequency brain waves/oscillations may represent beta and gammawaves. The neural modules 502 and 504 communicate with one another overlong-distance communications links (as denoted at 510 and 512). Thecommunications links 510, 512 between distributed neural modules 502,504 occur through the use of low frequency brain waves (e.g. delta,Theta and Alpha waves). The communication between modules 502, 504utilizes nesting or cross frequency coupling between the low frequencybrain waves (traveling between distributed neural modules) and the highfrequency brain waves (within corresponding neural modules). In thismanner, transient coherence or phase synchronization binds distributedneural assemblies/modules within the brain through dynamic (andpotentially long-range) connections. Nested therapy may be utilized tofacilitate long-distance communication links. In accordance withembodiments herein, nested stimulation waveforms may be delivereddirectly or indirectly to one or more distributed neural modules 502,504.

FIG. 6 illustrates a model reflecting the memory functionality of abrain. Memory has spatial and temporal characteristics 602 and 604.Memories are encoded through low frequency coupling betweenparahippocampal area 612, frontal area 608 and parietal (PFC) area 610.The spatial and temporal characteristics 602, 604 of memory aremultiplexed along common pathways through different frequencies. Forexample, the spatial characteristics 602 of memory are carried withinthe delta wave frequency band, while the temporal characteristics 604 ofmemory are carried within the Alpha wave frequency band. Nested therapymay be utilized to facilitate spatial and/or temporal characteristicsfor memories.

FIGS. 7A and 7B illustrate models proposed, in the 2007 Jensen paper,regarding computational roles for cross-frequency interactions betweentheta and gamma oscillations by means of phase coding. FIG. 7Aillustrates a model for working memory, in which individual memoryrepresentations are activated repeatedly in theta cycles. Each memoryrepresentation is represented by a subset of neurons in the networkfiring synchronously. Because different representations are activated indifferent gamma cycles, the gamma rhythm serves to keep the individualmemories segmented in time. As reported by Jensen, the number of gammacycles per theta cycle determines the span of the working memory. FIG.7B illustrates a model accounting for theta phase precession in rats.Positional information is passed to the hippocampus, which activates therespective place cell representations and provokes the prospectiverecall of upcoming positions. In each theta cycle, time-compressedsequences are recalled at the rate of one representation per gammacycle.

FIG. 8A illustrates an example of a nested stimulation waveform that maybe delivered in connection with nested therapies to brain tissue (orbrain tissue) of interest in accordance with embodiments herein. In FIG.8A, the nested stimulation waveform 802 includes multiple pulse bursts804 that are separated from one another by an inter-burst delay 808.Each of the pulse bursts 804 includes a series of individual pulses orspikes 810. The pulses 810 are delivered over a burst length 816 inconnection with an individual pulse bursts 804. The rate at which theindividual pulses 810 are delivered within a pulse bursts 804 isdetermined based on a pulse rate 812 (denoted as a bracket extendingbetween successive positive peaks of adjacent successive pulses 810).

FIG. 8A also illustrates a timeline extending along a horizontal axiswith various points in time noted along the nested stimulation waveform802. Each of the successive pulse bursts 804 are initiated at starttimes T10, T20 and T30, respectively. The interval between successivestart times (e.g. T10 and T-20) represents the burst to burst period814. The timeline also illustrates examples of the timing between pulses810 within an individual pulse burst (e.g. 804). For example, pulse peaktimes T1-T5 are illustrated as aligned with the peak positive point ofeach pulse 810. The pulse rate 812 corresponds to the pulse to pulseperiod 814.

The nested stimulation waveform may be decomposed into at least twoprimary waveform components, generally denoted as a carrier waveform 820and a high-frequency waveform 830. In accordance with embodimentsherein, the high frequency waveform is defined to correspond to highfrequency physiologic neural oscillations associated with the braintissue of interest, while the low frequency waveform is defined tocorrespond to low frequency physiologic neural oscillations associatedwith the brain tissue of interest. Optionally, one of the carrier andhigh frequency waveforms may be defined to differ from the low and highfrequency physiologic neural oscillations. For example, the highfrequency waveform may be defined to correspond to a physiologic beta orgamma wave, while the carrier waveform is defined to be independent of aphysiologic deta, theta or alpha wave. Alternatively, the high frequencywaveform may be defined to be independent of a physiologic beta or gammawave, while the carrier waveform is defined to correspond to aphysiologic deta, theta or alpha wave.

The carrier wave 820 may represent a non-sinusoidal waveform similar toa square wave, but with only positive or only negative wave segments822. In the example of FIG. 8A, the carrier wave 820 includes a seriesof positive wave segments 822 that are defined by parameters, such as apredetermined amplitude 824, segment width 826, inter segment delay 828,among other parameters. The segment width 826 corresponds to the burstlength 816, while the inter segment delay 828 corresponds to theinterburst delay 808. The segment amplitude 824 defines an averageamplitude for each pulse burst 804.

The high-frequency waveform 830 includes a series of bursts 832. Withineach burst 832, the waveform 830 oscillates periodically by switchingbetween positive and negative amplitudes 834 and 835 at a selectfrequency 838. The high-frequency waveform 830 represents anintermittent waveform in that successive adjacent bursts 832 areseparated by an interburst delay 836 which corresponds to the interburstdelay 808 and inter segment delay 828. The high-frequency waveform 830is defined by various parameters such as the frequency 138, amplitudes834, 835, interburst delay 836.

The high-frequency waveform 830 is combined with the carrier waveform820 to form the nested stimulation waveform 802. The parameters of thehigh-frequency and carrier waveforms 830 and 820 may be adjusted toachieve various effects. As one example, the parameters may be adjustedto achieve cross frequency coupling with neural oscillations ofinterest. As one example, the parameters may be adjusted to entrainneural oscillations of interest. For example, the frequency, phase andamplitude of the carrier waveform 820 may be managed to entrain neuraloscillations associated with brain tissue of interest, such as tissueassociated with sensory, motor or cognitive processing. The carrierwaveform 820 may entrain neural oscillations to the temporal structuredefined by the carrier waveform 820 such as to facilitate selectiveattention in connection with certain psychiatric disorders (e.g.schizophrenia, dyslexia, attention deficit/hyperactivity disorder).Additionally or alternatively, the high-frequency waveform 830 may bemanaged to entrain neural oscillations associated with the brain regionof interest. For example, the frequency, phase, amplitude as well asother parameters may be adjusted for the high-frequency waveform 830 toobtain entrainment of the neural oscillations of interest.

The characteristics discussed herein in connection with FIG. 8Arepresent non-limiting examples of therapy parameters that may be variedto define different nested therapies (e.g., different carrier waveformsand different high frequency waveforms). For example, a non-limitinglist of potential therapy parameters include pulse amplitude, pulsefrequency, pulse to pulse period, the number of pulses in each burst,burst length, interburst delay, the number of pulse bursts in eachnested stimulation waveform and the like. The pulse bursts may includepulses having a frequency corresponding to high frequency intrinsicneural oscillations exhibited by normal/physiologic brain tissue ofinterest. The pulse bursts are separated from one another with a burstto burst period that corresponds to a frequency of the low-frequencyintrinsic neural oscillations exhibited by normal/physiologic braintissue of interest.

The nested stimulation waveform combines the carrier waveform and highfrequency waveform in a predetermined manner. For example, the carrierand high-frequency waveforms may be combined utilizing one of thefollowing types of cross frequency coupling: power to power; phase topower; phase to phase; phase to frequency; power to frequency andfrequency to frequency. Optionally, the carrier and high-frequencywaveforms are combined through phase to power cross frequency coupling,in which the phase of the carrier waveform modulates the power of thehigh-frequency waveform. For example, the waveforms 820 and 830 may becombined in the manners discussed herein in connection with FIG. 4.

As one example, first parameters may be set to define the carrierwaveform to correspond to physiologic neural oscillations in the thetawave frequency band, while second parameters may be set to define thehigh-frequency waveform to correspond to physiologic neural oscillationsin the gamma wave frequency band. As explained herein, the nestedstimulation waveform may be defined to entrain and modulate the neuraloscillations in the gamma wave frequency band in connection with atleast one of sensory, motor, and cognitive events. Optionally, thenested stimulation waveform may be managed in connection with a patternof interest in neural oscillations through cross frequency couplingbetween theta and gamma waves associated with the brain tissue ofinterest.

As explained herein, the brain tissue of interest may correspond to onebrain region or comprise distributed neural modules located in separateregions of the brain. In accordance with embodiments herein methods andsystems may manage the nested stimulation waveform in connection withcross frequency coupling between neural oscillations associated with oneor distributed neural modules that exhibit long-distance communicationover neural oscillations within at least one of delta, theta and alphawave frequency bands.

In accordance with embodiments herein, methods and system measureintrinsic neural oscillations, determine whether the nested stimulationwaveform is achieving a desired modulation (e.g., entrainment) of theintrinsic neural oscillations, and adjust at least one of the first andsecond parameters to maintain the desired modulation (e.g., entrainment)of the intrinsic neural oscillations. The intrinsic neural oscillationsmay exhibit pathologic behavior or patterns. The nested stimulationwaveform is adjusted until the intrinsic neural oscillation exhibits aphysiologic behavior or pattern.

Optionally, the nested stimulation waveform may be comprised of morethan two waveform components. For example, a hierarchy of nestedwaveform components may be generated, such as with a base or carrierwaveform component, an intermediate waveform component and ahigh-frequency waveform component. By way of example only, the basewaveform component may defined to correspond to physiologic neuraloscillations associated with ultra-slow waves, delta waves, theta wavesand the like. The intermediate waveform component may be defined tocorrespond to physiologic neural oscillations associated with thetawaves, alpha waves, beta waves, gamma waves and the like. Thehigh-frequency waveform component may be defined correspond tophysiologic neural oscillations associated with beta waves, gamma waves,sigma waves and ultrafast waves. Optionally, more than three waveformcomponents may be combined within a nested hierarchy.

As one example, different carrier waveforms may be used based on thelocation at which the nested stimulation is delivered. For example, thecarrier waveform may vary based on whether the stimulation site fortissue of interest represents brain tissue, peripheral neuronal tissueand/or central neuronal tissue. Neuronal tissue includes any tissueassociated with the peripheral nervous system or the central nervoussystem. Peripheral neuronal tissue can include a nerve root or rootganglion or any neuronal tissue that lies outside the brain, brainstemor spinal cord.

Optionally, the nested stimulation waveform may be comprised of waveformcomponents associated with waves or frequency bands that are separatedfrom one another, along the frequency spectrum, in a non-adjacentmanner. For example, the waveform components may correspond to frequencyranges that are distributed in a non-successive manner. For example, thecarrier waveform component may correspond to neural oscillations in thedelta wave range, while the high-frequency waveform componentcorresponds to neural oscillations in the beta or gamma range. Asanother example, the carrier waveform component may correspond to neuraloscillations in the theta wave range, while the high-frequency waveformcomponent corresponds to neural oscillations in the beta, gamma orultrafast wave ranges.

While the primary examples provided herein are described in connectionwith carrier waveforms associated with the delta and theta wave ranges,it is understood that the carrier waveform component may correspond toneural oscillations in higher wave ranges. For example, the carrierwaveform component may correspond to neural oscillations in the beta,gamma and even the higher ultrafast wave ranges. By way of example only,it may be desirable to utilize carrier waveform components within thehigher range of us in connection with stimulation along the spinal cordand/or dorsal root ganglion.

Optionally, more than one carrier wave component may be included in anested stimulation waveform.

FIG. 8B illustrates an example of a nested stimulation waveform that maybe delivered in connection with nested therapies to brain tissue (orbrain tissue) of interest in accordance with embodiments herein. In FIG.8B, the nested stimulation waveform 842 includes multiple pulse bursts844 that are separated from one another by an inter-burst delay 848.Each of the pulse burst 844 includes a series of individual pulses orspikes 850. The pulses 850 are delivered over a burst length 856 inconnection with an individual pulse burst 844. The rate at which theindividual pulses 850 are delivered within a pulse burst 844 isdetermined based on a pulse rate 862 (denoted as a bracket extendingbetween successive positive peaks of adjacent successive pulses 810. Thenested stimulation waveform 842 includes a low frequency carrierwaveform 853 and a high frequency waveform that defines thecharacteristics of the pulses 850.

FIG. 8C illustrates an alternative example of a nested stimulationwaveform that may be delivered in connection with nested therapies tobrain tissue (or brain tissue) of interest in accordance withembodiments herein. In FIG. 8C, the nested stimulation waveform 852includes multiple pulse bursts 854 that are separated from one anotherby an inter-burst delay 858. Each of the pulse burst 854 includes aseries of individual pulses or spikes 860. The pulses 810 are deliveredover a burst length 866 in connection with an individual pulse burst854. The rate at which the individual pulses 860 are delivered within apulse burst 854 is determined based on a pulse rate 862 (denoted as abracket extending between successive positive peaks of adjacentsuccessive pulses 860).

The nested stimulation waveform 852 is decomposed into a carrierwaveform 870 and a high-frequency waveform 880. The carrier wave 870 mayrepresent a sinusoidal waveform having positive and negative wavesegments 872. The positive and negative wave segments 822 are defined bya predetermined amplitude 874 and segment width 876 among otherparameters.

The high-frequency waveform 880 includes a series of bursts 882. Withineach burst 882, the waveform 880 oscillates periodically by switchingbetween positive and negative amplitudes 884 and 885 at a selectfrequency 888. The high-frequency waveform 880 represents anintermittent waveform in that successive adjacent bursts 882 areseparated by an interburst delay 886 which corresponds to the interburstdelay 858.

The high-frequency waveform 880 is combined with the carrier waveform870 to form the nested stimulation waveform 852. The parameters of thehigh-frequency and carrier waveforms 880 and 870 are adjusted to entrainand/or achieve cross frequency coupling with neural oscillations ofinterest. For example, the frequency, phase and amplitude of the carrierwaveform 870 may be managed to entrain neural oscillations associatedwith a brain region of interest, such as a brain region associated withsensory, motor or cognitive processing. The carrier waveform 870 mayentrain neural oscillations to the temporal structure defined by thecarrier waveform 870 such as to facilitate selective attention inconnection with certain psychiatric disorders (e.g. schizophrenia,dyslexia, attention deficit/hyperactivity disorder). Additionally oralternatively, the high-frequency waveform 880 may be managed to entrainneural oscillations associated with the brain region of interest. Forexample, the frequency, phase, amplitude as well as other parameters maybe adjusted for the high-frequency waveform 880 to obtain entrainment ofthe neural oscillations of interest.

The carrier and high-frequency waveforms 870 and 880 may be combinedutilizing one of the following types of cross frequency coupling: powerto power; phase to power; phase to phase; phase to frequency; power tofrequency and frequency to frequency. For example, the waveforms 870 and880 may be combined in the manner discussed herein in connection withFIG. 4. As one example, the carrier and high-frequency waveforms 870 and880 are combined through phase to power cross frequency coupling (asillustrated in connection with the waveform 405 in FIG. 4), in which thephase of the carrier waveform modulates the power of the high-frequencywaveform.

FIG. 9 illustrates alternative nested stimulation waveforms that may beutilized in accordance with embodiments herein. The nested stimulationwaveforms 902-912 may be delivered from multiple electrode combinationsalong the lead. The nested stimulation waveform 902 includes a carrierwaveform that is cross frequency coupled to a high frequency waveform toform multiple (e.g. three) pulse bursts 922 separated by an inter-burstinterval 924. The pulse burst 922 include a series of pulses 926 havinga common polarity (e.g. all positive pulses or all negative pulses).

The nested stimulation waveform 904 includes a pair of pulse bursts 932separated by an interburst interval 934. Each pulse burst 932 includes aseries of pulses 936 (e.g. three) that have a common polarity. Thenested stimulation waveform 906 includes a single pulse burst 942 havinga series of pulses 946, each of which is bipolar (e.g. extends betweenpositive and negative polarities). The pulses 946 have one of twostates/voltage levels, namely a positive pulse amplitude and a negativepulse amplitude that are common.

The stimulation waveform 908 includes a pair of pulse bursts 952separated by an inter-burst interval 954. Each pulse burst 952 includesmultiple pulses 956 that are bipolar (extending between positive andnegative polarities). The pulses 956 vary between more than two statesor voltage levels, namely first and second positive voltages 957-958 andfirst and second negative voltages 959 and 960. Optionally, additionalvoltage levels/states may be utilized and the positive and negativevoltage levels need not be common.

The nested stimulation waveform 910 includes pulse burst 962A-962D thatare separated by an interburst interval 964. The interburst intervals964 may differ from one another or be common. The pulse bursts 962A and962C have similar positive and negative amplitudes, while the pulsebursts 962B (positive) and 962D (negative) are monopolar and differentfrom one another. The nested stimulation waveform 912 illustrates asingle pulse burst 972 that has a carrier wave component (as denoted byenvelope 973 in dashed lines) that is modulated by a higher frequencycomponent (as denoted by solid lines 975). Optionally, the nestedstimulation waveform may be varied from the foregoing examples.Additionally, separate and distinct nested stimulation waveforms may bedelivered from different electrode combinations at non-overlappingdistinct points in time.

FIG. 10 illustrates a process for managing delivery of nestedstimulation waveforms to tissue of interest in accordance withembodiments herein. The operations of FIG. 10 may be implemented by oneor more processors, such as within an implantable medical device,external programmer, another external device and the like. The IMD,external programmer or other external device are coupled to a leadhaving at least one stimulation electrode that is implanted at a targetposition proximate to nervous tissue of interest.

At 1002, the IMD (processor) manages a switch circuit therein to connectthe pulse generator to a select electrode combination as defined by aprogrammed therapy parameter set. At 1002, the IMD also determines thenested stimulation waveform to be utilized. The stimulation waveform isdefined by one or more parameters forming a therapy parameter set (TPS).The IMD (processor) manages the pulse generator in the IMD to generatethe nested stimulation waveform by combining predetermined carrier andhigh frequency waveforms. Examples of parameters within a TPS include,but are not limited to pulse amplitude, pulse width, interpulse delay,number of pulses per burst, pulse frequency, burst frequency, burst toburst frequency, pulse frequency, burst length and burst period for theplurality of pulse bursts. Other examples are discussed herein.

At 1004, the IMD delivers a nested stimulation waveform to the selectelectrode combination within the array of electrodes located proximateto nervous tissue of interest. The stimulation waveform is delivered toat least one stimulation electrode combination on the lead. Ascontemplated in embodiments herein, a predetermined stimulation site fortissue of interest can include brain tissue, peripheral neuronal tissueand/or central neuronal tissue. Neuronal tissue includes any tissueassociated with the peripheral nervous system or the central nervoussystem. Peripheral neuronal tissue can include a nerve root or rootganglion or any neuronal tissue that lies outside the brain, brainstemor spinal cord. At 1006, the IMD determines whether the therapy iscomplete. When the therapy is complete, the process ends. Otherwise, theprocess continues to 1010.

At 1010, the IMD determines whether the nested stimulation waveformcontinues to have an intended effect (e.g., entrain) on the intrinsicneural oscillations for the tissue of interest. For example, the IMD maydetermine whether the intrinsic neural oscillations remain in phase withthe nested stimulation waveform. When the intrinsic neural oscillationsremain entrained (e.g. in phase or at a select phase shift relative to)the nested stimulation waveform, entrainment or another desired effectmay be determined to exist. Other characteristics, besides or inaddition to phase may be utilized to determine whether the stimulationwaveform modifies the neural oscillations in a desired manner. Forexample, the IMD may measure intrinsic neural oscillations and determinewhether the nested stimulation waveform is achieving entrainment of theintrinsic neural oscillations.

At 1012, the IMD (processor) determines whether to adjust at least oneof the first and second parameters to maintain entrainment of theintrinsic neural oscillations. The IMD determines whether to use thesame nested stimulation waveform or to use a different nestedstimulation waveform and/or exhibits a desired frequency, amplitude,etc. For example, when entrainment continues to occur at 1010, it may bedesirable to continue to apply the same nested stimulation waveform.Alternatively, when, at 1010, it is determined that the nestedstimulation waveform is not achieving entrainment (or has lostentrainment), it may be desirable to change the nested stimulationwaveform. A change in the nested stimulation waveform may be very minor,such as a slight phase shift. Alternatively or in addition, the changein the stimulation waveform may be substantial. The nested stimulationwaveform may change one or more characteristics, such as the frequencyof the carrier waveform, the frequency of the high-frequency component,as well as other parameters described herein. Additionally oralternatively, the form of cross frequency coupling may be changes. Forexample, in one iteration through the operations of FIG. 10, the carrierand high frequency waveforms may be combined utilizing phase to powercross frequency coupling. However, at 1010, it may be determined thatthe nested stimulation waveform is not achieving a desired result (e.g.,entrainment). Consequently, at 1012, it may be determined to change (at1014) the nested stimulation waveform by changing the type of crossfrequency coupling, such as to switch from phase to phase or power topower coupling.

When the same waveform is to be utilized, flow moves to 1016. Otherwise,flow advances to 1014. At 1014, the IMD obtains the next or successivenested stimulation waveform to be utilized. Thereafter, flow moves to1016. At 1016, the IMD (processor) determines whether to use the sameelectrode combination as with the prior cycle. If so, flow returns to1004. Otherwise, flow advances to 1018. At 1018, the IMD obtains thenext electrode combination to be utilized. At 1020, the IMD manages theswitch to connect the pulse generator to the corresponding nextelectrode combination. Thereafter, flow returns to 1004 where the nextnested stimulation waveform is delivered.

The operations of FIG. 10 are continuously repeated indefinitely,periodically or for a select period of time. In accordance with theforegoing manner, the IMD sequentially delivering (through theoperations at 1004-1020) successive nested stimulation waveforms tosuccessive electrode combinations within the array of electrodes, thefirst and successive nested stimulation waveforms including at least oneseries of pulses having a pulse amplitude and pulse frequency. The IMDdelays delivery of the successive nested stimulation waveforms by theentrainment delay at 1010. The IMD manages at least one of the therapyparameters of the first and successive nested stimulation waveforms toexcite the nervous tissue of interest.

In the foregoing process of FIG. 10, the IMD operates in accordance withthe preprogrammed therapy parameter set that is defined by a physician,clinician, the patient or otherwise. The therapy parameter set may bedetermined in various manners, such as based upon data collected fromnumerous studies, prior patients, a present patient over time and thelike.

FIG. 11 illustrates a process for collecting and analyzing neuraloscillations in connection with identifying desired nested stimulationwaveforms in accordance with embodiments herein. At 1102, the methoddefines one or more nested stimulation waveform to be used. The nestedstimulation waveform is defined by one or more parameters forming atherapy parameter set (TPS), wherein at least first parameters define acarrier waveform and at least second parameters define a high frequencywaveform.

At 1104, the method senses intrinsic neural oscillation baseline signalsby collecting neural oscillation signals for a data collection windowwhile baseline conditions are maintained (e.g., no external input isapplied to the patient). The oscillation baseline signals are indicativeof the brain wave activity exhibited naturally or inherently by braintissue of interest at one or more target sites. The oscillation baselinesignals, collected over a single data collection window, represent anoscillation baseline sample for a single time interval, where theoscillation baseline sample is indicative of a baseline oscillationpattern generated by the brain tissue of interest.

Throughout the embodiments described herein, the same electrodes may beused for sensing and stimulation. Alternatively, one group of electrodesmay be used for sensing, while a different group of electrodes are usedfor stimulation. For example, the sensing electrodes may be spaced apartalong the lead from the stimulation electrodes. Optionally, the sensingelectrodes may be provided on a separate lead unique and distinct fromthe lead that includes the stimulation electrodes. In variousembodiments herein, electrodes and leads may be used for stimulationand/or sensing, provided that the electrodes are configured to belocated at a desired proximity relative to a target site or tissue ofinterest. Additionally or alternatively, the lead to be used for sensingmay include micro electrodes (alone or in combination with conventionalelectrodes), where the micro electrodes that are configured to be placedimmediately adjacent brain tissue of interest.

At 1106, the oscillation baseline signal is analyzed to define baselinefeatures within the morphology of the oscillation signal. By way ofexample, the oscillation baseline signals may be processed through afast Fourier transform to separate the frequency components therein. Thefrequency components within a frequency band of interest (e.g. the bandassociated with the delta, theta, alpha, beta or gamma waves) areanalyzed to define one or more parameters of interest associated withthe morphology of the frequency band of interest.

For example, the baseline features may represent the phase, frequencyand amplitude of the neural oscillations collected in the beta wavefrequency range. Additionally or alternatively, the baseline featuresmay represent the phase, frequency and amplitude of the neuraloscillations within the delta wave frequency range. As another example,the baseline features may represent an amplitude of peaks, a number ofpeaks, a number of direction changes and the like within the baselinesample collected over the data collection window. The baseline sample(s)and their features described above are stored in memory. The baselinesamples may be used over time as a reference such as in connection withdefining a nested stimulation therapy, and/or for comparison with latercollected baseline samples, such as to determine when a patient'sinherent level of oscillation activity is increasing or decreasing.Optionally, the operations at 1104 and 1106 may be omitted entirely.

At 1108, the method delivers the nested stimulation waveform to at leastone electrode based on the TPS defined at 1102. The stimulation waveformis delivered to at least one stimulation electrode on the lead. At 1110,the method applies a predetermined external sensory stimulation that isconfigured to induce select neural oscillation patterns within the braintissue of interest. The reference input may represent a predetermineddegree or amount of touch. Optionally, the reference input maycorrespond to the patient speaking, viewing a picture, holding anobject, performing a physical motion, or any other external inputintended to otherwise cause the select neural oscillation pattern.Optionally, the reference input may correspond to the patient undergoinga recognition or memory exercise. The reference input is applied in arepeatable manner and may be applied repeatedly at different times whileintrinsic neural oscillation signals are collected in connection withdifferent TPS.

At 1112, the method senses neural oscillation signals and collects theneural oscillation signals for a data collection window. The neuraloscillation signals are indicative of the brain wave activity exhibitedby nervous tissue of interest at the target position in response to thereference or noxious input. The neural oscillation signals, collectedover a single data collection window, represent an oscillation samplefor a single time interval, where the oscillation sample is indicativeof a responsiveness of the fibers of interest when a predeterminedexternal sensory stimulation is delivered. The neural oscillationsignals are saved as an oscillation sample.

At 1114, the method analyzes the neural oscillation signal (e.g., theoscillation sample) to obtain neural oscillation data associated withthe TPS. The neural oscillation data corresponds to brain wave activityfor the tissue of interest. The analysis at 1114 is repeated numeroustimes to obtain a collection of neural oscillation data associated witha group or multiple TPS. In the embodiment illustrated in FIG. 11, theoperation at 1114 may be implemented during each iteration through theoperation at 1108-1120. At 1114, the method also saves the neuraloscillation data along with the values for the corresponding therapyparameter set, such as in a memory of the IPG, external programmer orother external device. The neural oscillation data and the associatedtherapy parameter set are saved, over time, in connection withdelivering therapy based on multiple therapy parameter sets, therebydeveloping a therapy/oscillatory interaction history for the patient.

At 1116, the method determines whether a sufficient number ofoscillation samples have been collected (and analyzed). When asufficient number of oscillation samples have been collected, flow movesto 1122. When it is determined that additional oscillation samplesshould be collected, flow moves along 1118 to 1120. At 1120, the methodchanges a value for one or more of the parameters within the therapyparameter set. The change at 1120 may be performed in a predeterminedsystematic stepwise manner. For example, each parameter within thetherapy parameter set may be incrementally adjusted by a select amountduring separate iterations through the operations at 1108-1116. As anexample, during iterations 1-11, the method may only change theamplitude of the stimulation waveform between low, medium and highamplitudes, while maintaining constant all other parameters within theTPS. After cycling through each of the pulse amplitudes of interest, thepulse amplitude may be reset to the low level for iterations 4-6, duringwhich the pulse width is changed from short to medium to long. Duringiterations 7-9, the pulse amplitude may be set to the medium level,while the pulse width is again changed from short to medium to long,while all other parameters are maintained constant. The foregoingprocess may be repeated until each, or at least a select portion, of thepotential permutations and combinations of levels for the parameters areused during the operations at 1108-1116 to form the group of TPS forwhich the collection of neural oscillations is accumulated.

Alternatively or additionally, not all permutations and combinations ofparameter levels may be used. For example, a physician or other user mayselect (and/or program) individual TPS of interest to be tested as thegroup of TPS. For example, the operations at 1108-1116 may only berepeated for 5 to 10 or 20 different TPS, even though many morepermutations and combinations of levels for the various parametersexist. The change performed at 1120 may be based on pre-stored settingsor may represent an input from a physician or other user duringoperation.

Optionally, the amount of change during each iteration through 1120 mayvary, such as with larger step changes made during initial iterationsand smaller step changes made during later iterations. Optionally, theamount of change at 1120 may be based on a difference between the neuraloscillations and the threshold. For example, when the neuraloscillations substantially exceeds the threshold, larger changes may beapplied to one or more parameters at 1120. As the difference between theneural oscillations and threshold decreases, the incremental change inthe one or more parameters is changed by similarly/proportionallydecreasing amounts. Following 1120, flow returns to 1108.

At 1122, the method selects a candidate TPS from the multiple or groupof TPS based on one or more criteria of interest. For example, when thecriteria of interest represents a threshold or predetermined range forthe neural oscillations, the candidate TPS may be selected as the TPSthat resulted in neural oscillations that satisfy the threshold orpredetermined range. For example, when the criteria of interestrepresents sensory activity, at 1122, the method may identify theoscillation sample for which the lowest or smallest amount of neuraloscillations was identified. The lowest or smallest amount of activityis measured relative to the neural oscillations of the other oscillationsamples. The method cross references oscillation sample, that exhibitsthe lowest or smallest amount of neural oscillations, to thecorresponding therapy parameter set which is designated as the candidateTPS. As one example, the selection at 1122 may seek to optimize thecandidate TPS to define as a burst stimulation waveform that affords anoscillation activity below a threshold or within a range, collectivelyreferred to as a result of interest, without inducing paresthesia. Oncea candidate TPS is selected, the candidate TPS is used for subsequenttherapy for a period of time, for example until it becomes desirable torepeat the process of FIG. 11 to determine a new candidate TPS.

FIG. 12 illustrates a process for defining a nested stimulation waveformbased on neural oscillations in accordance with embodiments herein. At1202, a collection of intrinsic neural oscillations is obtained. Forexample, the collection of intrinsic neural oscillations may beprerecorded from a collection of patients, prerecorded at multiplepoints in time from an individual patient, or recorded during a surgicaloperation in which a system as described herein is being implanted.

At 1204, the neural oscillations are processed by a processor toseparate the frequency components of interest therein. For example, theneural oscillations may be passed through a fast Fourier transform andone or more bandpass filters to separate the various frequencycomponents associated with each type of brain wave activity of interest.As noted in connection with FIG. 3, separate frequency ranges exist fordelta waves, theta waves, alpha waves, beta waves and gamma waves. Aseparate bandpass filter may be shaped by the processor to isolate eachof the brain wave frequency ranges.

At 1206, the processor identifies a carrier frequency component and ahigh frequency component of interest that are cross frequency coupled toone another. For example, the delta wave frequency component may beidentified as the carrier frequency component, while the theta or alphawave frequency component is identified as the high-frequency component.As another example, the theta wave frequency component may be identifiedas the carrier frequency component while the beta or gamma wavefrequency components are identified as the high-frequency component.

At 1208, the processor analyzes the carrier frequency component forfeatures of interest (e.g. phase, frequency, amplitude). At 1210, theprocess analyzes the high-frequency component for one or more featuresof interest. At 1212, the processor defines a carrier waveform componentto be used in connection with generating a nested stimulation waveformbased on the carrier FOls. At 1214, the process defines a high-frequencywaveform component to be used in connection with generating the nestedstimulation waveform based on the high-frequency FOls.

The operations of FIG. 12 may be repeated numerous times in connectionwith different collections of oscillation signals to define multipletherapy parameter sets used in connection with generating differenttypes of nested stimulation waveforms. For example, the therapyparameter sets may identify numerous types of carrier waveformcomponents, as well as numerous types of high-frequency waveformcomponents, such as illustrated in FIGS. 8A-8C and 9.

The operations of FIG. 12 may be carried out by one or more processorsof the IMD, an external device, or otherwise.

Electrical Stimulation Devices

FIGS. 1A-1B illustrate example neurological stimulation (NS) systems 10for electrically stimulating a predetermined site area to treat one ormore neurological disorders or conditions. In general terms, stimulationsystem 10 includes an implantable pulse generating source or electricalIMD 12 (generally referred to as an “implantable medical device” or“IMD”) and one or more implantable electrodes or electrical stimulationleads 14 for applying nested stimulation pulses to a predetermined site.In operation, both of these primary components are implanted in theperson's body, as discussed below. In certain embodiments, IMD 12 iscoupled directly to a connecting portion 16 of stimulation lead 14. Inother embodiments, IMD 12 is incorporated into the stimulation lead 14and IMD 12 instead is embedded within stimulation lead 14. For example,such a stimulation system 10 may be a Bion® stimulation systemmanufactured by Advanced Bionics Corporation. Whether IMD 12 is coupleddirectly to or embedded within the stimulation lead 14, IMD 12 controlsthe stimulation pulses transmitted to one or more stimulation electrodes18 located on a stimulating portion 20 of stimulation lead 14,positioned in communication with a predetermined site, according tosuitable therapy parameters (e.g., duration, amplitude or intensity,frequency, pulse width, firing delay, etc.).

As contemplated in embodiments herein, a predetermined stimulation sitefor tissue of interest can include either peripheral neuronal tissueand/or central neuronal tissue. Neuronal tissue includes any tissueassociated with the peripheral nervous system or the central nervoussystem. Peripheral neuronal tissue can include a nerve root or rootganglion or any neuronal tissue that lies outside the brain, brainstemor spinal cord. Peripheral nerves can include, but are not limited toolfactory nerve, optic, nerve, oculomotor nerve, trochlear nerve,trigeminal nerve, abducens nerve, facial nerve, vestibulocochlear(auditory) nerve, glossopharyngeal nerve, vagal nerve, accessory nerve,hypoglossal nerve, suboccipital nerve, the greater occipital nerve, thelesser occipital nerve, the greater auricular nerve, the lesserauricular nerve, the phrenic nerve, brachial plexus, radial axillarynerves, musculocutaneous nerves, radial nerves, ulnar nerves, mediannerves, intercostal nerves, lumbosacral plexus, sciatic nerves, commonperoneal nerve, tibial nerves, sural nerves, femoral nerves, glutealnerves, thoracic spinal nerves, obturator nerves, digital nerves,pudendal nerves, plantar nerves, saphenous nerves, ilioinguinal nerves,gentofemoral nerves, and iliohypogastric nerves.

Central neuronal tissue includes brain tissue, spinal tissue orbrainstem tissue. Brain tissue can include thalamus/sub-thalamus, basalganglia, hippocampus, amygdala, hypothalamus, mammilary bodies,substantla nigra or cortex or white matter tracts afferent to orefferent from the abovementioned brain tissue, inclusive of the corpuscallosum. Spinal tissue can include the ascending and descending tractsof the spinal cord, more specifically, the ascending tracts of thatcomprise intralaminar neurons or the dorsal column. The brainstem tissuecan include the medulla obiongata, pons or mesencephalon, moreparticular the posterior pons or posterior mesencephalon, Lushka'sforamen, and ventrolateral part of the medulla oblongata.

A doctor, the patient, or another user of IMD 12 may directly or indirectly input therapy parameters to specify or modify the nature of thestimulation provided.

In FIG. 1B, the IMD 12 includes an implantable wireless receiver. Anexample of a wireless receiver may be one manufactured by AdvancedNeuromodulation Systems, Inc., such as the Renew® System, part numbers3408 and 3416. In another embodiment, the IMD can be optimized for highfrequency operation as described in U.S. Provisional Application Ser.No. 60/685,036, filed May 26, 2005, entitled “SYSTEMS AND METHODS FORUSE IN PULSE GENERATION,” which is incorporated herein by reference. Thewireless receiver is capable of receiving wireless signals from awireless transmitter 22 located external to the person's body. Thewireless signals are represented in FIG. 1B by wireless link symbol 24.A doctor, the patient, or another user of IMD 12 may use a controller 26located external to the person's body to provide control signals foroperation of IMD 12. Controller 26 provides the control signals towireless transmitter 22, wireless transmitter 22 transmits the controlsignals and power to the wireless receiver of IMD 12, and IMD 12 usesthe control signals to vary the signal parameters of electrical signalstransmitted through electrical stimulation lead 14 to the stimulationsite. Thus, the external controller 26 can be for example, a handheldprogrammer, to provide a means for programming the IMD. An examplewireless transmitter may be one manufactured by Advanced NeuromodulationSystems, Inc., such as the Renew® System, part numbers 3508 and 3516.

The IMD 12 applies burst stimulation to brain tissue of a patient.Specifically, the IMD includes a microprocessor and a pulse generationmodule. The pulse generation module generates the electrical pulsesaccording to a defined pulse width and pulse amplitude and applies theelectrical pulses to defined electrodes. The microprocessor controls theoperations of the pulse generation module according to softwareinstructions stored in the device.

The IMD 12 can be adapted by programming the microprocessor to deliver anumber of spikes (relatively short pulse width pulses) that areseparated by an appropriate interspike interval. Thereafter, theprogramming of the microprocessor causes the pulse generation module tocease pulse generation operations for an interburst interval. Theprogramming of the microprocessor also causes a repetition of the spikegeneration and cessation of operations for a predetermined number oftimes. After the predetermined number of repetitions has been completedwithin a nested stimulation waveform, the microprocessor can cause burststimulation to cease for an amount of time (and resume thereafter).Also, in some embodiments, the microprocessor could be programmed tocause the pulse generation module to deliver a hyperpolarizing pulsebefore the first spike of each group of multiple spikes.

The microprocessor can be programmed to allow the variouscharacteristics of the burst stimulus to be set by a physician to allowthe burst stimulus to be optimized for a particular pathology of apatient. For example, the spike amplitude, the interspike interval, theinterburst interval, the number of bursts to be repeated in succession,the electrode combinations, the firing delay between nested stimulationwaveforms delivered to different electrode combinations, the amplitudeof the hyperpolarizing pulse, and other such characteristics could becontrolled using respective parameters accessed by the microprocessorduring burst stimulus operations. These parameters could be set todesired values by an external programming device via wirelesscommunication with the implantable neuromodulation device.

In another embodiment, the IMD 12 can be implemented to apply burststimulation using a digital signal processor and one or severaldigital-to-analog converters. The burst stimulus waveform could bedefined in memory and applied to the digital-to-analog converter(s) forapplication through electrodes of the medical lead. The digital signalprocessor could scale the various portions of the waveform in amplitudeand within the time domain (e.g., for the various intervals) accordingto the various burst parameters.

FIG. 1C depicts an NS system 100 that delivers nested therapies inaccordance with embodiments herein. For example, the NS system 100 maybe adapted to stimulate spinal cord tissue, peripheral nervous tissue,deep brain tissue, or any other suitable nervous/brain tissue ofinterest within a patient's body.

The NS system 100 may be controlled to deliver various types of nestedstimulation therapy, such as high frequency neurostimulation therapies,burst neurostimulation therapies and the like. High frequencyneurostimulation includes a continuous series of monophasic or biphasicpulses that are delivered at a predetermined frequency. Burstneurostimulation includes short sequences of monophasic or biphasicpulses, where each sequence is separated by a quiescent period. Ingeneral, nested therapies include a continuous, repeating orintermittent pulse sequence delivered at a frequency and amplitudeconfigured to avoid inducing (or introduce a very limited) paresthesia.

The NS system 100 may deliver nested stimulation therapy based onpreprogrammed therapy parameters. The therapy parameters may include,among other things, pulse amplitude, pulse polarity, pulse width, pulsefrequency, interpulse interval, inter burst interval, electrodecombinations, firing delay and the like. Optionally, the NS system 100may represent a closed loop neurostimulation device that is configuredto provide real-time sensing functions from a lead. The configuration ofthe lead sensing electrodes may be varied depending on the neuronalanatomy of the sensing site(s) of interest. The size and shape ofelectrodes is varied based on the implant location. The electroniccomponents within the NS system 100 are designed with both stimulationand sensing capabilities, including alternative nested stimulationtherapy, such as burst mode, high frequency mode and the like.

The NS system 100 includes an implantable medical device (IMD) 150 thatis adapted to generate electrical pulses for application to tissue of apatient. The IMD 150 typically comprises a metallic housing or can 158that encloses a controller 151, pulse generating circuitry 152, a chargestorage circuit 153, a battery 154, a far-field and/or near fieldcommunication circuitry 155, battery charging circuitry 156, switchingcircuitry 157, memory 158 and the like. The charge storage circuit 153may represent one or more capacitors and/or battery cells that storecharge used to produce the therapies described herein. The pulsegenerating circuitry 152, under control of the controller 151, managesdischarge of the charge storage circuit 153 to shape the morphology ofthe waveform delivered while discharging energy. The switching circuitry157 connects select combinations of the electrodes 121 a-d to the pulsegenerating circuitry 152 thereby directing the stimulation waveform to adesired electrode combination. As explained herein, the switchingcircuitry 157 successively connects the pulse generating circuitry 152to successive electrode combinations 123 and 125. The components 151-158are also within the IMD 12 (FIGS. 1A and 1B).

The controller 151 typically includes one or more processors, such as amicrocontroller, for controlling the various other components of thedevice. Software code is typically stored in memory of the IMD 150 forexecution by the microcontroller or processor to control the variouscomponents of the device.

The IMD 150 may comprise a separate or an attached extension component170. If the extension component 170 is a separate component, theextension component 170 may connect with the “header” portion of the IMD150 as is known in the art. If the extension component 170 is integratedwith the IMD 150, internal electrical connections may be made throughrespective conductive components. Within the IMD 150, electrical pulsesare generated by the pulse generating circuitry 152 and are provided tothe switching circuitry 157. The switching circuitry 157 connects tooutputs of the IMD 150. Electrical connectors (e.g., “Bal-Seal”connectors) within the connector portion 171 of the extension component170 or within the IMD header may be employed to conduct variousstimulation pulses. The terminals of one or more leads 110 are insertedwithin connector portion 171 or within the IMD header for electricalconnection with respective connectors. Thereby, the pulses originatingfrom the IMD 150 are provided to the lead 110. The pulses are thenconducted through the conductors of the lead 110 and applied to tissueof a patient via stimulation electrodes 121 a-d that are coupled toblocking capacitors. Any suitable known or later developed design may beemployed for connector portion 171.

The stimulation electrodes 121 a-d may be positioned along a horizontalaxis 102 of the lead 110, and are angularly positioned about thehorizontal axis 102 so the stimulation electrodes 121 a-d do notoverlap. The stimulation electrodes 121 a-d may be in the shape of aring such that each stimulation electrode 121 a-d continuously coversthe circumference of the exterior surface of the lead 110. Adjacentstimulation electrodes 121 a-d are separated from one another bynon-conducting rings 112, which electrically isolate each stimulationelectrode 121 a-d from an adjacent stimulation electrode 121 a-d. Thenon-conducting rings 112 may include one or more insulative materialsand/or biocompatible materials to allow the lead 110 to be implantablewithin the patient. Non-limiting examples of such materials includepolyimide, polyetheretherketone (PEEK), polyethylene terephthalate (PET)film (also known as polyester or Mylar), polytetrafluoroethylene (PTFE)(e.g., Teflon), or parylene coating, polyether bloc amides,polyurethane. The stimulation electrodes 121 a-d may be configured toemit the pulses in an outward radial direction proximate to or within astimulation target. Additionally or alternatively, the stimulationelectrodes 121 a-d may be in the shape of a split or non-continuous ringsuch that the pulse may be directed in an outward radial directionadjacent to the stimulation electrodes 121 a-d. The stimulationelectrodes 121 a-d deliver tonic, high frequency and/or burst nestedstimulation waveforms as described herein. Optionally, the electrodes121 a-d may also sense neural oscillations and/or sensory actionpotential (neural oscillation signals) for a data collection window.

The lead 110 may comprise a lead body 172 of insulative material about aplurality of conductors within the material that extend from a proximalend of lead 110, proximate to the IMD 150, to its distal end. Theconductors electrically couple a plurality of the stimulation electrodes121 to a plurality of terminals (not shown) of the lead 110. Theterminals are adapted to receive electrical pulses and the stimulationelectrodes 121 a-d are adapted to apply the pulses to the stimulationtarget of the patient. Also, sensing of physiological signals may occurthrough the stimulation electrodes 121 a-d, the conductors, and theterminals. It should be noted that although the lead 110 is depictedwith four stimulation electrodes 121 a-d, the lead 110 may include anysuitable number of stimulation electrodes 121 a-d (e.g., less than four,more than four) as well as terminals, and internal conductors.Additionally or alternatively, various sensors (e.g., a positiondetector, a radiopaque fiducial) may be located near the distal end ofthe lead 110 and electrically coupled to terminals through conductorswithin the lead body 172.

Although not required for any embodiments, the lead body 172 of the lead110 may be fabricated to flex and elongate upon implantation oradvancing within the tissue (e.g., nervous tissue) of the patienttowards the stimulation target and movements of the patient during orafter implantation. By fabricating the lead body 172, according to someembodiments, the lead body 172 or a portion thereof is capable ofelastic elongation under relatively low stretching forces. Also, afterremoval of the stretching force, the lead body 172 may be capable ofresuming its original length and profile.

By way of example, the IMD 12, 150 may include a processor andassociated charge control circuitry as described in U.S. Pat. No.7,571,007, entitled “SYSTEMS AND METHODS FOR USE IN PULSE GENERATION,”which is expressly incorporated herein by reference. Circuitry forrecharging a rechargeable battery (e.g., battery charging circuitry 156)of an IMD using inductive coupling and external charging circuits aredescribed in U.S. Pat. No. 7,212,110, entitled “IMPLANTABLE DEVICE ANDSYSTEM FOR WIRELESS COMMUNICATION,” which is expressly incorporatedherein by reference. An example and discussion of “constant current”pulse generating circuitry (e.g., pulse generating circuitry 152) isprovided in U.S. Patent Publication No. 2006/0170486 entitled “PULSEGENERATOR HAVING AN EFFICIENT FRACTIONAL VOLTAGE CONVERTER AND METHOD OFUSE,” which is expressly incorporated herein by reference. One ormultiple sets of such circuitry may be provided within the IMD 12, 150.Different burst and/or high frequency pulses on different stimulationelectrodes may be generated using a single set of the pulse generatingcircuitry using consecutively generated pulses according to a“multi-stimset program” as is known in the art. Complex pulse parametersmay be employed such as those described in U.S. Pat. No. 7,228,179,entitled “Method and apparatus for providing complex tissue stimulationpatterns,” and Intentional Patent Publication Number WO 2001/093953 A1,entitled “NEUROMODULATION THERAPY SYSTEM,” which are expresslyincorporated herein by reference. Alternatively, multiple sets of suchcircuitry may be employed to provide pulse patterns (e.g., tonicstimulation waveform, burst stimulation waveform) that include generatedand delivered stimulation pulses through various stimulation electrodesof one or more leads as is also known in the art. Various sets ofparameters may define the pulse characteristics and pulse timing for thepulses applied to the various stimulation electrodes. Although constantcurrent pulse generating circuitry is contemplated for some embodiments,any other suitable type of pulse generating circuitry may be employedsuch as constant voltage pulse generating circuitry.

The controller 151 delivers a nested stimulation waveform to at leastone electrode combination located proximate to nervous tissue ofinterest, the nested stimulation waveform including a series of pulsesconfigured to excite the nested C-fibers of the nervous tissue ofinterest, the nested stimulation waveform defined by therapy parameters.The controller 151 may deliver the nested stimulation waveform based onpreprogrammed therapy parameters. The preprogrammed therapy parametersmay be set based on information collected from numerous past patientsand/or test performed upon an individual patient during initial implantand/or during periodic checkups.

Optionally, the controller 151 senses intrinsic neural oscillations fromat least one electrode on the lead. Optionally, the controller 151analyzes the intrinsic neural oscillations signals to obtain brainactivity data. The controller 151 determines whether the activity datasatisfies a criteria of interest. The controller 151 adjusts at leastone of the therapy parameters to change the nested stimulation waveformwhen the activity data does not satisfy the criteria of interest. Thecontroller 151 iteratively repeats the delivering operations for a groupof TPS. The IMD selects a candidate TPS from the group of TPS based on acriteria of interest. The therapy parameters define at least one of aburst stimulation waveform or a high frequency stimulation waveform. Thecontroller 151 may repeat the delivering, sensing and adjustingoperations to optimize the nested stimulation waveform. The analyzingoperation may include analyzing a feature of interest from a morphologyof the neural oscillation signal over time, counting a number ofoccurrences of the feature of interest that occur within the signal overa predetermined duration, and generating the activity data based on thenumber of occurrences of the feature of interest.

Memory 158 stores software to control operation of the controller 151for nested stimulation therapy as explained herein. The memory 158 alsostores neural oscillation signals, therapy parameters, neuraloscillation activity level data, sensation scales and the like. Forexample, the memory 158 may save neural oscillation activity level datafor various different therapies as applied over a short or extendedperiod of time. A collection of neural oscillation activity level datais accumulated for different therapies and may be compared to identifyhigh, low and acceptable amounts of sensory activity.

A controller device 160 may be implemented to charge/recharge thebattery 154 of the IMD 150 (although a separate recharging device couldalternatively be employed) and to program the IMD 150 on the pulsespecifications while implanted within the patient. Although, inalternative embodiments separate programmer devices may be employed forcharging and/or programming the NS system 100. The controller device 160may be a processor-based system that possesses wireless communicationcapabilities. Software may be stored within a non-transitory memory ofthe controller device 160, which may be executed by the processor tocontrol the various operations of the controller device 160. A “wand”165 may be electrically connected to the controller device 160 throughsuitable electrical connectors (not shown). The electrical connectorsmay be electrically connected to a telemetry component 166 (e.g.,inductor coil, RF transceiver) at the distal end of wand 165 throughrespective wires (not shown) allowing bi-directional communication withthe IMD 150. Optionally, in some embodiments, the wand 165 may compriseone or more temperature sensors for use during charging operations.

The user may initiate communication with the IMD 150 by placing the wand165 proximate to the NS system 100. Preferably, the placement of thewand 165 allows the telemetry system of the wand 165 to be aligned withthe far-field and/or near field communication circuitry 155 of the IMD150. The controller device 160 preferably provides one or more userinterfaces 168 (e.g., touchscreen, keyboard, mouse, buttons, or thelike) allowing the user to operate the IMD 150. The controller device160 may be controlled by the user (e.g., doctor, clinician) through theuser interface 168 allowing the user to interact with the IMD 150. Theuser interface 168 may permit the user to move electrical stimulationalong and/or across one or more of the lead(s) 110 using differentstimulation electrode 121 combinations, for example, as described inU.S. Patent Application Publication No. 2009/0326608, entitled “METHODOF ELECTRICALLY STIMULATING TISSUE OF A PATIENT BY SHIFTING A LOCUS OFSTIMULATION AND SYSTEM EMPLOYING THE SAME,” which is expresslyincorporated herein by reference.

Also, the controller device 160 may permit operation of the IMD 12, 150according to one or more therapies to treat the patient. Each therapymay include one or more sets of stimulation parameters of the pulseincluding pulse amplitude, pulse width, pulse frequency or inter-pulseperiod, firing delay, pulse repetition parameter (e.g., number of timesfor a given pulse to be repeated for respective stimset during executionof program), biphasic pulses, monophasic pulses, etc. The IMD 150modifies its internal parameters in response to the control signals fromthe controller device 160 to vary the stimulation characteristics of thestimulation pulses transmitted through the lead 110 to the tissue of thepatient. NS systems, stimsets, and multi-stimset programs are discussedin PCT Publication No. WO 01/93953, entitled “NEUROMODULATION THERAPYSYSTEM,” and U.S. Pat. No. 7,228,179, entitled “METHOD AND APPARATUS FORPROVIDING COMPLEX TISSUE STIMULATION PATTERNS.” which are expresslyincorporated herein by reference.

FIGS. 2A-2I illustrate example stimulation leads 14 that may be used forelectrically stimulating the predetermined site to treat one or moreneurological disorders or conditions. As described above, each of theone or more stimulation leads 14 incorporated in stimulation systems 10,100 includes one or more stimulation electrodes 18 adapted to bepositioned in communication with the predetermined site and used todeliver the stimulation pulses received from IMD 12 (or pulse generatingcircuitry 157 in FIG. 1C). A percutaneous stimulation lead 14(corresponding to the lead 110 in FIG. 1C), such as example stimulationleads 14 a-d, includes one or more circumferential electrodes 18 spacedapart from one another along the length of stimulating portion 20 ofstimulation lead 14. Circumferential electrodes 18 emit electricalstimulation energy generally radially (e.g., generally perpendicular tothe axis of stimulation lead 14) in all directions. A laminotomy,paddle, or surgical stimulation lead 14, such as example stimulationleads 14 e-i, includes one or more directional stimulation electrodes 18spaced apart from one another along one surface of stimulation lead 14.Directional stimulation electrodes 18 emit electrical stimulation energyin a direction generally perpendicular to the surface of stimulationlead 14 on which they are located. Although various types of stimulationleads 14 are shown as examples, embodiments herein contemplatestimulation system 10 including any suitable type of stimulation lead 14in any suitable number. In addition, stimulation leads 14 may be usedalone or in combination. For example, medial or unilateral stimulationof the predetermined site may be accomplished using a single electricalstimulation lead 14 implanted in communication with the predeterminedsite in one side of the head, while bilateral electrical stimulation ofthe predetermined site may be accomplished using two stimulation leads14 implanted in communication with the predetermined site in oppositesides of the head.

In one embodiment, the stimulation source is transcutaneously incommunication with the electrical stimulation lead. In “transcutaneous”electrical nerve stimulation (TENS), the stimulation source is externalto the patient's body, and may be worn in an appropriate fanny pack orbelt, and the electrical stimulation lead is in communication with thestimulation source, either remotely or directly. In another embodiment,the stimulation is percutaneous. In “percutaneous” electrical nervestimulation (PENS), needles are inserted to an appropriate depth aroundor immediately adjacent to a predetermined stimulation site, and thenstimulated.

The IMD 12, 150 allow each electrode of each lead to be defined as apositive, a negative, or a neutral polarity. For each electrodecombination (e.g., the defined polarity of at least two electrodeshaving at least one cathode and at least one anode), an electricalsignal can have at least a definable amplitude (e.g., voltage), pulsewidth, and frequency, where these variables may be independentlyadjusted to finely select the sensory transmitting brain tissue requiredto inhibit transmission of neuronal signals. Generally, amplitudes,pulse widths, and frequencies are determinable by the capabilities ofthe neurostimulation systems, which are known by those of skill in theart. Voltages that may be used can include, for example about 0.5 toabout 10 volts, more preferably about 1 to about 10 volts.

In embodiments herein, the therapy parameter of signal frequency isvaried to achieve a burst type rhythm, or burst mode stimulation.Generally, the burst stimulus frequency may be in the range of about 1Hz to about 100 Hz, more particular, in the range of about 1 Hz to about12 Hz, and more particularly, in the range of about 1 Hz to about 4 Hz,4 Hz to about 7 Hz or about 8 Hz to about 12 Hz for each burst. Eachburst stimulus comprises at least two spikes, for example, each burststimulus can comprise about 2 to about 100 spikes, more particularly,about 2 to about 10 spikes. Each spike can comprise a frequency in therange of about 50 Hz to about 1000 Hz, more particularly, in the rangeof about 200 Hz to about 500 Hz. The frequency for each spike within aburst can be variable, thus it is not necessary for each spike tocontain similar frequencies, e.g., the frequencies can vary in eachspike. The inter-spike interval can be also vary, for example, theinter-spike interval, can be about 0.5 milliseconds to about 100milliseconds or any range therebetween.

The burst stimulus is followed by an inter-burst interval, during whichsubstantially no stimulus is applied. The inter-burst interval hasduration in the range of about 5 milliseconds to about 5 seconds, morepreferably, 10 milliseconds to about 300 milliseconds. It is envisionedthat the burst stimulus has a duration in the range of about 10milliseconds to about 5 seconds, more particular, in the range of about250 msec to 1000 msec (1-4 Hz burst firing), 145 msec to about 250 msec(4-7 Hz,), 145 msec to about 80 msec (8-12 Hz) or 1 to 5 seconds inplateau potential firing. The burst stimulus and the inter-burstinterval can have a regular pattern or an irregular pattern (e.g.,random or irregular harmonics). More specifically, the burst stimuluscan have a physiological pattern or a pathological pattern.

It is envisaged that the patient will require intermittent assessmentwith regard to patterns of stimulation. Different electrodes on the leadcan be selected by suitable computer programming, such as that describedin U.S. Pat. No. 5,938,690, which is incorporated by reference here infull. Utilizing such a program allows an optimal stimulation pattern tobe obtained at minimal voltages. This ensures a longer battery life forthe implanted systems.

FIGS. 2A-2I respectively depict stimulation portions for inclusion atthe distal end of lead. Stimulation portion depicts a conventionalstimulation portion of a “percutaneous” lead with multiple ringelectrodes. Stimulation portion depicts a stimulation portion includingseveral segmented electrodes. Example fabrication processes aredisclosed in U.S. patent application Ser. No. 12/895,096, entitled,“METHOD OF FABRICATING STIMULATION LEAD FOR APPLYING ELECTRICALSTIMULATION TO TISSUE OF A PATIENT,” which is incorporated herein byreference. Stimulation portion includes multiple planar electrodes on apaddle structure.

A. Deep Brain Stimulation

In certain embodiments, for example, patients may have an electricalstimulation lead or electrode implanted into the brain. The anatomicaltargets or predetermined site may be stimulated directly or affectedthrough stimulation in another region of the brain.

In embodiments herein, the predetermined site or implant sites include,but are not limited to thalamus/sub-thalamus, basal ganglia,hippocampus, amygdala, hypothalamus, mammilary bodies, substantia nigraor cortex or white matter tracts afferent to or efferent from theabovementioned brain tissue, inclusive of the corpus callosum. Stillfurther, the predetermined site may comprise the auditory cortex and/orsomatosensory cortex in which the stimulation devices is implantedcortically.

Once electrical stimulation lead 14, 110 has been positioned in thebrain, lead 14, 110 is uncoupled from any stereotactic equipmentpresent, and the cannula and stereotactic equipment are removed. Wherestereotactic equipment is used, the cannula may be removed before,during, or after removal of the stereotactic equipment. Connectingportion 16 of electrical stimulation lead 14, 110 is laid substantiallyflat along the skull. Where appropriate, any burr hole cover seated inthe burr hole may be used to secure electrical stimulation lead 14, 110in position and possibly to help prevent leakage from the burr hole andentry of contaminants into the burr hole.

Once electrical stimulation lead 14, 110 has been inserted and secured,connecting portion of lead 14, 110 extends from the lead insertion siteto the implant site at which IMD 12, 150 is implanted. The implant siteis typically a subcutaneous pocket formed to receive and house IMD 12,150. The implant site is usually positioned a distance away from theinsertion site, such as near the chest, below the clavicle oralternatively near the buttocks or another place in the torso area. Onceall appropriate components of stimulation system 10, 100 are implanted,these components may be subject to mechanical forces and movement inresponse to movement of the person's body. A doctor, the patient, oranother user of IMD 12, 150 may directly or in directly input signalparameters for controlling the nature of the electrical stimulationprovided.

Although example steps are illustrated and described, embodiments hereincontemplate two or more steps taking place substantially simultaneouslyor in a different order. In addition, embodiments herein contemplateusing methods with additional steps, fewer steps, or different steps, solong as the steps remain appropriate for implanting an examplestimulation system 10, 100 into a person for electrical stimulation ofthe person's brain.

Brainstem Stimulation

The stimulation system 10, 100, described above, can be implanted into aperson's body with stimulation lead 14 located in communication with apredetermined brainstem tissue and/or area. Such systems that can beused are described in WO2004062470, which is incorporated herein byreference in its entirety.

The predetermined brainstem tissue can be selected from medullaoblongata, pons or mesencephalon, more particular the posterior pons orposterior mesencephalon, Lushka's foramen, and ventrolateral part of themedulla oblongata.

Implantation of a stimulation lead 14 in communication with thepredetermined brainstem area can be accomplished via a variety ofsurgical techniques that are well known to those of skill in the art.For example, an electrical stimulation lead can be implanted on, in, ornear the brainstem by accessing the brain tissue through a percutaneousroute, an open craniotomy, or a burr hole. Where a burr hole is themeans of accessing the brainstem, for example, stereotactic equipmentsuitable to aid in placement of an electrical stimulation lead 14 on,in, or near the brainstem may be positioned around the head. Anotheralternative technique can include, a modified midline or retrosigmoidposterior fossa technique.

In certain embodiments, electrical stimulation lead 14 is located atleast partially within or below the aura mater adjacent the brainstem.Alternatively, a stimulation lead 14 can be placed in communication withthe predetermined brainstem area by threading the stimulation lead upthe spinal cord column, as described above, which is incorporatedherein.

As described above, each of the one or more leads 14 incorporated instimulation system 10 includes one or more electrodes 18 adapted to bepositioned near the target brain tissue and used to deliver electricalstimulation energy to the target brain tissue in response to electricalsignals received from IMD 12. A percutaneous lead 14 may include one ormore circumferential electrodes 18 spaced apart from one another alongthe length of lead 14. Circumferential electrodes 18 emit electricalstimulation energy generally radially in all directions and may beinserted percutaneously or through a needle. The electrodes 18 of apercutaneous lead 14 may be arranged in configurations other thancircumferentially, for example as in a “coated” lead 14. A laminotomy orpaddle style lead 14, such as example leads 14 e-i, includes one or moredirectional electrodes 18 spaced apart from one another along onesurface of lead 14. Directional electrodes 18 emit electricalstimulation energy in a direction generally perpendicular to the surfaceof lead 14 on which they are located. Although various types of leads 14are shown as examples, embodiments herein contemplate stimulation system10 including any suitable type of lead 14 in any suitable number,including three-dimensional leads and matrix leads as described below.In addition, the leads may be used alone or in combination.

Yet further, a stimulation lead 14 can be implanted in communicationwith the predetermined brainstem area by a using stereotactic proceduressimilar to those described above, which are incorporated herein, forimplantation via the cerebrum.

Still further, a predetermined brainstem area can be in directlystimulated by implanting a stimulation lead 14 in communication with acranial nerve (e.g., olfactory nerve, optic, nerve, oculomoter nerve,trochlear nerve, trigeminal nerve, abducent nerve, facial nerve,vestibulocochlear nerve, glossopharyngeal nerve, vagal nerve, accessorynerve, and the hypoglossal nerve) as well as high cervical nerves(cervical nerves have anastomoses with lower cranial nerves) such thatstimulation of a cranial nerve in directly stimulates the predeterminedbrainstem tissue. Such techniques are further described in U.S. Pat.Nos. 6,721,603; 6,622,047; and 5,335.657, and U.S. ProvisionalApplication 60/591,195 entitled “Stimulation System and Method forTreating a Neurological Disorder” each of which are incorporated hereinby reference.

Although example steps are illustrated and described, embodiments hereincontemplate two or more steps taking place substantially simultaneouslyor in a different order. In addition, embodiments herein contemplateusing methods with additional steps, fewer steps, or different steps, solong as the steps remain appropriate for implanting stimulation system10 into a person for electrical stimulation of the predetermined site.

In accordance with embodiments herein, methods and devices affordactivation of the anti-nociceptive system of the human body. Forexample, the methods and systems may utilize nested stimulationtherapies to treat chronic neuropathic pain, various syndromes,fibromyalgia, and in general nociceptive pain. By activating pleasureresponses of the human body, methods and devices are provided to treatdepression, social isolation or deprivation, distress, anxiety, autismand the like. Further, by activating pleasure responses of the humanbody, methods and devices are provided to treat homeostatic imbalances,such as irritable bowel syndrome (IBS), urinary urgency, pain, tinnitus,addiction, obesity and the like.

A. Sensory Disorders 1. Tinnitus

In the auditory system, tonic firing transmits the contents of auditoryinformation, while burst firing transmit the valence or importanceattached to that sound (Lisman 1997; Sherman 2001; Swadlow and Gusev2001). Repetitive stimulus presentation results in decreased neuronalresponse to that stimulus, known as auditory habituation at the singlecell level (Ulanovsky et al., 2003), auditory mismatch negativity atmultiple cell level (Naatanen et al., 1993; Ulanovsky et al., 2003).

Tinnitus is a noise in the ears, often described as ringing, buzzing,roaring, or clicking Subjective and objective forms of tinnitus exist,with objective tinnitus often caused by muscle contractions or otherinternal noise sources in the area proximal to auditory structures. Incertain cases, external observers can hear the sound generated by theinternal source of objective tinnitus. In subjective forms, tinnitus isaudible only to the subject. Tinnitus varies in perceived amplitude,with some subjects reporting barely audible forms and others essentiallydeaf to external sounds and/or incapacitated by the intensity of theperceived noise.

Tinnitus is usually constantly present, e.g., a non-rational valence isattached to the internally generated sound, and there is no auditoryhabituation to this specific sound, at this specific frequency. Thus,tinnitus is the result of hyperactivity of lesion-edge frequencies, andauditory mismatch negativity in tinnitus patients is specific forfrequencies located at the audiometrically normal lesion edge (Weisz2004).

As pathological valence of the tinnitus sound is mediated by burstfiring, burst firing is increased in tinnitus in the extralemniscalsystem (Chen and Jastreboff 1995; Eggermont and Kenmochi 1998; Eggermont2003), in the inner hair cells (Puel 1995; Puel et al., 2002), theauditory nerve (Moller 1984), the dorsal and external inferiorcolliculus (Chen and Jastreboff 1995), the thalamus (Jeanmonod, Magninet al., 1996) and the secondary auditory cortex (Eggermont and Kenmochi1998; Eggermont 2003). Furthermore, quinine, known to generate tinnitus,induces an increased regularity in burst firing, at the level of theauditory cortex, inferior colliculus and frontal cortex (Gopal and Gross2004). It is contemplated that tinnitus can only become conscious if anincreased tonic firing rate is present in the lemniscal system,generating the sound. This increased firing activity has beendemonstrated in the lemniscal dorsal cochlear nucleus (Kaltenbach,Godfrey et al., 1998; Zhang and Kaltenbach 1998; Kaltenbach and Afman2000; Brozoski, Bauer et al., 2002; Zacharek et al., 2002; Kaltenbach etal., 2004), inferior colliculus (Jastreboff and Sasaki 1986; Jastreboff,Brennan et al., 1988; Jastreboff 1990) (Gerken 1996) and primaryauditory cortex (Komiya, 2000). Interestingly, not only tonic firing isincreased generating the tinnitus sound, but also the burst firing (Ochiand Eggermont 1997) (keeping it conscious) at a regular basis.Repetitive burst firing is known to generate tonic gamma band activity(Gray and Singer 1989; Brumberg, 2000). Thus, it is envisioned thatembodiments herein can be used to modify burst firing, thus modifyingtonic gamma activity.

Burst mode firing boosts the gain of neural signaling of Important ornovel events by enhancing transmitter release and enhancing dendriticdepolarization, thereby increasing synaptic potentiation. Conversely,single spiking mode may be used to dampen neuronal signaling and may beassociated with habituation to unimportant events (Cooper 2002). It isbelieved that the main problem in tinnitus is that the internallygenerated stimulus does not decay due to the presence of regularbursting activity telling the cortex this signal is important and has toremain conscious.

Thus, in embodiments herein, it is envisioned that the neuromodulationsystem can attack either of these two pathways: slowing down tonicfiring in the lemniscal system (below 40 Hz) or removing the valenceattached to it by the extralemniscal system by suppressing the regularbursting rhythm, thereby treating tinnitus. Yet further, theneuromodulation system of embodiments herein can also make the tinnitusdisappear via auditory habituation. Suppressing the rhythmic burstfiring in the frontal cortex may alter the emotional affect given to thetinnitus, with the tinnitus persisting, a situation known by many peopleperceiving tinnitus, but without much influence on their daily life.Such methods of treating tinnitus are further described in U.S.Provisional Applications entitled “Deep Brain Stimulation to TreatTinnitus” filed Oct. 21, 2004; “Peripheral Nerve Stimulation to TreatTinnitus” filed Oct. 21, 2004; and “Dorsal Column Stimulation to TreatTinnitus” filed Oct. 21, 2004, each of which is incorporated byreference in its entirety. 2. Phantom Pain

In phantom pain the same is noted as in Parkinson's Disease (PD) andtinnitus. In humans, the tonic firing rate increases (Yamashiro et al.,2003), as well as the amount of burst firing in the deafferentedreceptive fields (Rinaidi et al., 1991; Jeanmonod et al., 1996;Radhakrishnan et al., 1999) in the somatosensory thalamic nuclei(Rinaldi et al., 1991; Lenz et al., 1998), as well as activity in the inthe intralaminar nuclei (Weigel and Krauss 2004). Synchrony in firing isalso increased. This is similar to what is seen in animal neuropathicpain models (Lombard and Besson 1989; Nakamura and Atsuta 2004)(Yamashiro et al., 1991). These results suggest that in pain decreasedspike frequency adaptation and increased excitability develops afterinjury to sensory neurons. Through decreased Ca.sup.2+ Influx, the cellbecomes less stable and more likely to initiate or transmit bursts ofaction potentials (McCallum et al., 2003).

Thus, it is envisioned that that the neuromodulation system or method ofembodiments herein will alter or disrupt the regular bursting rhythmassociated with the phantom pain.

3. Motor Disorders

In Parkinson's disease (PD), the striatum is viewed as the principalinput structure of the basal ganglia, while the internal pallidalsegment (GPi) and the substantia nigra pars reticulata (SNr) are outputstructures. Input and output structures are linked via a monosynaptic“direct” pathway and a polysynaptic “indirect” pathway involving theexternal pallidal segment (GPe) and the subthalamic nucleus (STN).According to current schemes, striatal dopamine (DA) enhancestransmission along the direct pathway (via D1 receptors), and reducestransmission over the indirect pathway (via D2 receptors) (Wichmann andDeLong 2003).

Increased firing rates are noted in PD, both in the globus pallidus(Magnin et al., 2000) and the subthalamic nucleus (Levy et al., 2002)and is reversed in successful STN stimulation in PD (Welter et al.,2004; Boraud et al., 1996). Synchronization between firing rates isimportant: lower frequency oscillations facilitate slow idling rhythmsin the motor areas of the cortex, whereas synchronization at highfrequency restores dynamic task-related cortical ensemble activity inthe gamma band (Brown 2003). In PD, a (hyper)synchronization is relatedto tremor (Levy et al., 2002), similarly to what is seen in the animalParkinson model (Raz et al., 2000; Nini et al., 1995).

Two or more firing modes exist in the subthalamic nucleus: tonic firing(68%), phasic or burst firing (25%) and phasic-tonic (7%)(Magarinos-Ascone et al., 2002).

In the monkey MPTP Parkinson model, burst firing, which occurs at 4 to 8Hz, increases in the STN and Gpi in comparison to normal firing (from69% and 78% in STN and GPi to 79% and 89%, respectively) (Bergman etal., 1994), as well as burst duration, without increase in the amount ofspikes per burst (Bergman et al., 1994). Abnormally increased tonic andphasic activity in STN leads to abnormal GPI activity and is a majorfactor in the development of parkinsonian motor signs (Wichmann et al.,1994). The percentage of cells with 4- to 8-Hz periodic activitycorrelates with tremor and is significantly increased from 2% to 16% inSTN and from 0.6% to 25% in GPi with the MPTP treatment (Bergman et al.,1994). These cells are also recorded in humans with PD (Hutchison etal., 1997). Furthermore, synchronization increases, e.g., a decrease inindependent activity (Raz et al., 2000; Nini et al., 1995), both intonically firing cells (Raz et al., 2001) and burst firing cells. Thus,it is envisioned that that the neuromodulation or stimulation system ormethod of embodiments herein will alter or disrupt or override theregular bursting rhythm associated with PD.

Other movement disorders, for example, chorea, Huntington's chorea,hemiballism and parkinsonian tremor all differ in the amount ofregularity in their muscle contractions. (Hashimoto and Yanagisawa1994). The regularities of interval, amplitude, rise time, and EMGactivity differs within order of regularity, such PD, vascular chorea,Huntington chorea and hemiballism being least regular (Hashimoto andYanagisawa 1994). However, in chorea (Hashimoto et al., 2001),hemiballism (Postuma and Lang 2003) and Huntington's disease (Cubo etal., 2000), the firing rate might be decreased in contrast to PD. Burstdischarges are, however, correlated to the choreatic movements (Kanazawaet al., 1990), similarly to what is noted in PD (Bergman, Wichmann etal., 1994). Thus, the neuromodulation system and/or method ofembodiments herein is used to alter or disrupt the dysfunctional firingrate of the disease or condition.

B. Autonomic Disorders

The autonomic nervous system (ANS) is predominantly an efferent systemtransmitting impulses from the central nervous system (CNS) toperipheral organ systems. Its effects include control of heart rate andforce of contraction, constriction and dilatation of blood vessels,contraction and relaxation of smooth muscle in various organs, visualaccommodation, pupillary size and secretions from exocrine and endocrineglands. In addition to it being predominantly an efferent system, thereare some afferent autonomic fibers (e.g., transmit information from theperiphery to the CNS), which are concerned with the mediation ofvisceral sensation and the regulation of vasomotor and respiratoryreflexes, for example the baroreceptors and chemoreceptors in thecarotid sinus and aortic arch which are important in the control ofheart rate, blood pressure and respiratory activity. These afferentfibers are usually carried to the CNS by major autonomic nerves such asthe vagus, splanchnic or pelvic nerves, although afferent pain fibersfrom blood vessels may be carried by somatic nerves.

The ANS is divided into two separate divisions, the parasympathetic andsympathetic systems. This division is based on anatomical and functionaldifferences. Both of these systems consist of myelinated preganglionicfibres that make synaptic connections with unmyelinated postganglionicfibres, and it is these which then innervate the effector organ. Thesesynapses usually occur in clusters called ganglia. Most organs areinnervated by fibers from both divisions of the ANS, and the influenceis usually opposing (e.g., the vagus slows the heart, whilst thesympathetic nerves increase its rate and contractility), although it maybe parallel (e.g., the salivary glands).

The activity recorded from mammalian sympathetic nerves comes in bursts,which result from large numbers of fibers firing synchronously. Humansympathetic nerve activity behaves similarly. Vasomotor, cardiac andsudomotor nerve fibers all fire in bursts. Bursts in post-ganglionicnerves are driven by synchronously firing preganglionic neurons. Burstamplitude, which reflects the number of fibers firing together, andburst probability are controlled independently (McAllen and Malpas1997). The sympathetic nerve also fires in a 10 Hz tonic mode (Barman,Kitchens et al., 1997). This 10-Hz rhythm is also involved incardiovascular regulation, as blood pressure falls significantly whenthe 10-Hz rhythm is eliminated. Cardiac-related burst activity and 10-Hzrhythms are generated by different pools of brainstem neurons (Barman,Kitchens et al., 1997).

When electrical stimulation is applied to the sympathetic nerve, burststimulation is more powerful (vasoconstrictor) than tonic mode. Theamount of spikes per burst also determines the efficacy of stimulation(Ando, Imaizumi et al., 1993). The same is seen with electricalstimulation of the cervical sympathetic nerve trunk delivered at 50 Hzin bursts of 1 s every 10 s. Burst stimulation evoked a more copious,uniform and reproducible flow of saliva than when delivered at 10 Hzcontinuously (Anderson, Garrett et al., 1988). Similar superior resultswith burst stimulation have been obtained studying nasal mucosareactivity: both types of stimulation reduced nasal blood flow andvolume, but the responses were significantly larger with burststimulation at 0.59 Hz compared to tonic 0.59 Hz stimulation (Lacroix,Stjame et al., 1988).

In the parasympathetic system, burst firing and tonic firing co-exist.For example, one population of neurons responds with a brief burst ofaction potentials at the onset of the depolarization, accommodating tothe stimulus, and the other population responds with repetitive actionpotentials persisting throughout the duration of the stimulus, notaccommodating to the stimulus (Myers 1998; Bertrand 2004).

Burst stimulation at 0.1 Hz with 20 Hz spiking of the parasympatheticnerve results in a 200-fold more powerful enzyme induction than 2 Hztonic stimulation, when delivering the same amount of pulses (in thesublingual gland) (Nilsson, Rosengren et al., 1991). 1. Hypertension andHeart Rhythm Disorders

The nucleus of the solitary tract (NTS), a termination site for primaryafferent fibers from baroreceptors and other peripheral cardiovascularreceptors, and the paratrigeminal nucleus (Pa5) contain bloodpressure-sensitive neurons, some of which have rhythmic activity lockedto the cardiac cycle, making them key components of the central pathwayfor cardiovascular regulation. NTS and Pa5 baroreceptor-activatedneurons possess phasic discharge patterns locked to the cardiac cycle(Junior, Caous et al., 2004). The human insular cortex is involved incardiac regulation. The left insula is predominantly responsible forparasympathetic cardiovascular effects. On stimulation of the leftinsular cortex, parasympathetic tone increases resulting in bradycardiaand depressor responses more frequently than tachycardia and pressoreffects (p<0.005) (Oppenheimer, Gelb et al., 1992). The converse appliesfor the right insular cortex: stimulation of the human right insulaincreases sympathetic cardiovascular tone (Oppenheimer 1993). Acute leftinsular stroke increases basal cardiac sympathetic tone and isassociated with a decrease in randomness of heart rate variability(Oppenheimer, Kedem et al. 1996). Increased sympathoadrenal tone,resulting from damage to cortical areas involved in cardiac andautonomic control can induce cardiac damage by nonischemic mechanisms(Oppenheimer and Hachinski 1992).

Brain noradrenaline (NA) neurons in the locus coeruleus (LC) and majorparts of the SNS respond by burst activation in concert to stressfulstimuli implying novelty or fear. (Svensson 1987). In hypertension,burst firing is increased (Schlaich, Lambert et al., 2004) (Esler,Rumantir et al., 2001).

The autonomic nervous system plays an important role in the genesis ofvarious cardiac rhythm disorders. In patients with paroxysmal atrialfibrillation, it is important to distinguish vagally mediated fromadrenergically mediated atrial fibrillation. The former is considered torepresent a form of lone atrial fibrillation affecting particularlymales aged 40 to 50 years. The arrhythmic episodes manifest themselvesmost often during the night lasting from minutes to hours, whereas inadrenergic mediated atrial fibrillation, atrial fibrillation is oftenprovoked by emotional or physical stress. (Hohnloser, van de Loo et al.,1994)

Thus, hypertension (e.g., neurogenic hypertension) can be treated withburst stimulation of the left insula using the stimulation system ofembodiments herein. In a similar fashion, bradycardia can be treated byburst stimulation of the right insula as subjects with bradycardia havesignificantly higher metabolic activity in the right (p<0.0001) and inthe left temporal insula (p<0.015) than those with normal heart rates(Volkow, Wang et al., 2000). Lone atrial fibrillation can be treated byeither by left or rightsided burst stimulation depending on whether itis vagally or adrenergicly induced. 2. Sleep Apnea

Activity in the sympathetic nervous system is enhanced not only inobstructive apnea, but also in central and mixed apnea (Shimizu,Takahashi et al., 1997). Burst rate during apnea is higher in centralapneas than in obstructive apneas. Burst rate is the central componentof mixed apnea and the obstructive component of mixed apneas (Shimizu,Takahashi et al., 1997).

This intense sympathoexcitation is due to chronic or intermittenthypoxia (Cutler, Swift et al., 2004; Cutler, Swift et al., 2004).Pathological sympathoexcitation appears to depend on both recruitmentand increased burst firing frequency. In OSAS, also the amount of spikesper burst is increased, (Elam, McKenzie et al., 2002) and at night,arousal-induced reduction in sympathetic burst latency is noted (Xie,Skatrud et al., 1999).

Functional MRI or FMRI studies demonstrate reduced neural signals withinthe frontal cortex, anterior cingulate, cerebellar dentate nucleus,dorsal pons, anterior insula and lentiform nuclei. Signal increases inOSA over control subjects are seen in the dorsal midbrain, hippocampus,quadrangular cerebellar lobule, ventral midbrain and ventral pons(Macey, Macey et al., 2003). In the rat, the respiratory area in theanterior insular cortex consists of two distinct zones which overlap aregion modulating the gastrointestinal activity (Aleksandrov,Aleksandrova et al., 2000). In the more rostral area, there is adecrease in respiratory airflow and tidal volume with no alteration ofthe respiratory rate (the inhibition response), and in the other thereis an increase in respiratory rate and inspiratory airflow (theexcitation response).

Thus, embodiments herein can be used to activate respiration duringapneas by burst stimulation of the anterior insula.

C. Obesity

Food presentation in normal healthy, non-obese individuals significantlyincreases metabolism in the whole brain (24%, P<0.01), and these changesare largest in superior temporal, anterior insula, and orbitofrontalcortices (Wang, Volkow et al., 2004). Food-related visual stimuli elicitgreater responses in the amygdala, parahippocampal gyms and anteriorfusiform gyms when participants are in a hungry state relative to asatiated state (LaBar, Gitelman et al., 2001). Hunger is associated withsignificantly increased rCBF in the vicinity of the hypothalamus andinsular cortex and in additional paralimbic and limbic areas(orbitofrontal cortex, anterior cingulate cortex, and parahippocampaland hippocampal formation), thalamus, caudate, precuneus, putamen, andcerebellum (Tataranni, Gautier et al., 1999). Satiation is associatedwith increased rCBF in the vicinity of the ventromedial prefrontalcortex, dorsolateral prefrontal cortex, and inferior parietal lobule(Tataranni, Gautier et al., 1999). High-calorie foods yield significantactivation within the medial and dorsolateral prefrontal cortex,thalamus, hypothalamus, corpus callosum, and cerebellum. Low-caloriefoods yield smaller regions of focal activation within medialorbitofrontal cortex, primary gustatory/somatosensory cortex, andsuperior, middle, and medial temporal regions (Kiligore, Young et al.,2003). Activity within the temporo-insular cortex in normal appetitivefunction is associated with the desirability or valence of food stimuli,prior to ingestion (Gordon, Dougherty et al., 2000). When a food iseaten to satiety, its reward value decreases. Responses of gustatoryneurons in the secondary taste area within the orbitofrontal cortex aremodulated by hunger and satiety, in that they stop responding to thetaste of a food on which an animal has been fed to behavioral satiation,yet may continue to respond to the taste of other foods (Critchley andRolls 1996; O'Doherty, Rolls et al., 2000). In the OFC, the rCBFdecreases in the medial OFC and increases in the lateral OFC as thereward value of food changes from pleasant to aversive for non-liquid(Small, Zatorre et al., 2001) and liquid foods (Kringelbach, O'Dohertyet al., 2003). In the insular gustatory cortex, neuronal responses togustatory stimuli are not influenced by the normal transition fromhunger to satiety. This is in contrast to the responses of a populationof neurons recorded in the hypothalamus, which only respond to the tasteof food when the monkey is hungry (Yaxley, Rolls et al., 1988). Brainresponses to hunger/satiation in the hypothalamus, limbic/paralimbicareas (commonly associated with the regulation of emotion), andprefrontal cortex (thought to be involved in the inhibition ofinappropriate response tendencies) might be different in obese and leanindividuals (Del Parigi, Gautier et al., 2002). Compared with leanwomen, obese women have significantly greater increases in rCBF in theventral prefrontal cortex and have significantly greater decreases inthe paralimbic areas and in areas of the frontal and temporal cortex(Gautier, Del Parigi et al., 2001). In obese women, the rCBF is higherin the right parietal and temporal cortices during the food exposurethan in the control condition. In addition, in obese women theactivation of the right parietal cortex is associated with an enhancedfeeling of hunger when looking at food (Karhunen, Lappalainen et al.,1997). This significantly higher metabolic activity in the bilateralparietal somatosensory cortex is noted in the regions where sensation tothe mouth, lips and tongue are located. The enhanced activity insomatosensory regions involved with sensory processing of food in theobese subjects can make them more sensitive to the rewarding propertiesof food related to palatability and can be one of the variablescontributing to their excess food consumption (Wang, Volkow et al.,2002).

Based on the abovementioned model, the stimulation system and/or methodof embodiments herein can be used to produce burst stimulation ofthe—orbitofrontal cortex or—insula to treat obesity especially in thosepeople who are constant eaters rather than binge or high volume eaters.Other targets that can be stimulated are the dorsolateral prefrontalcortex, thalamus, hypothalamus, corpus callosum, and cerebellum, as wellas the medial orbitofrontal cortex, primary gustatory/somatosensorycortex, and superior, middle, and medial temporal regions and theamygdalohippocampal area and anterior cingulated area.

D. Cognitive and Psychological Disorders 1. Depression

In patients suffering from a depression, a hypometabolism andhypoperfusion localized to the left middorsolateral frontal cortex(MDLFC) is noted (Baxter, Schwartz et al., 1989; Brody, Saxena et al.,2001). Furthermore decreased neural activity in the MDLFC, aka thedorsolateral prefrontal cortex, is correlated with severity ofdepression (Bench, Friston et al., 1992; Bench, Friston et al., 1993;Dolan, Bench et al., 1994) and is reversed upon recovery from depression(Bench, Frackowiak et al., 1995). Electroencephalography demonstratesincreased alpha power. Alpha power is thought to be inversely related toneural activity in left frontal regions of the brains of depressedpatients (Bruder, Fong et al., 1997).

Metabolic activity in the ventral perigenual ACC is increased indepressed patients relative to control subjects (Videbech, Ravnkilde etal., 2001) and is positively correlated with severity of depression(Drevets 1999). Furthermore, neural activity in this region decreases inresponse to antidepressant treatment (Brody, Saxena et al., 2001).

The MDLFC occupies the middle frontal and superior frontal gyri andcomprises cytoarchitectonic areas 46 and 9/46 (middle frontal gyms) andarea 9 (superior frontal gyms) (Paus and Barrett 2004). The MDLFC hasconnections with sensory areas processing visual (prestriate andinferior temporal cortices), auditory (superior temporal cortex) andsomatosensory (parietal cortex) information (Petrides and Pandya 1999).The MDLFC also reciprocally connects with the anterior and, to a lesserextent, posterior cingulate cortices (Bates and Goldman-Rakic 1993).

Transcranial magnetic stimulation has been performed in the treatment ofdepression. The left MDLFC is the most common target for rTMS treatmentof depression (Paus and Barrett 2004), and rTMS of the left MDLFCmodulates the blood-flow response in the ACC (Barrett, Della-Maggiore etal., 2004; Paus and Barrett 2004). High-frequency (20 Hz) andlow-frequency (1 Hz) stimulation seem to have an opposite effect.High-frequency stimulation (HFS) increases and low-frequency stimulation(LFS) decreases cerebral blood flow (CBF) and/or glucose metabolism inthe frontal cortex and other linked brain regions (Speer, Kimbrell etal., 2000; Kimbrell, Little et al., 1999; and Post, Kimbrell et al.,1999).

Successful treatment of depression with TMS results in normalization ofhypoperfusion (with HFS) and normalization hyperperfusion (with LFS)(Kimbrell, Little et al., 1999). Thus, TMS treatment for depression canbe proposed using 20 Hz left frontal cortex (Kimbrell, Little et al.,1999; Paus and Barrett 2004) or 1 Hz right frontal cortex (Klein,Kreinin et al., 1999).

In the ACC of the rat, three kinds of burst firing is recorded. Rhythmicburst firing with inter-burst intervals of 80 and 200 ms andnon-rhythmic burst firing (Gemmell, Anderson et al., 2002). ACCstimulations evoke both tonic and burst reactions in the dorsolateralprefrontal cortex (Desiraju 1976). Similarly to other cortical areas,the dorsolateral prefrontal cortex has burst firing cells, tonic firingcells and mixed firing cells. Similarly to other areas, the burst firingnotices new incoming sensory (auditory, visual) information, and tonicfiring continues as long as the stimulus lasts (Ito 1982). TMS in burstmode is more powerful than TMS in tonic mode. For example, 20 seconds of5 Hz burst firing with 3 pulses at 50 Hz per burst have the same effectas 10 minutes 1 Hz tonic TMS.

Thus, the present stimulation system and/or method can be used to treatdepression. For example, a cortical electrode is implanted on the rightMDLFC and a 5 Hz burst mode is used to treat recurring depressions thatreact to a test stimulation with TMS. 2. Obsessive Convulsive Disorder

Obsessive-compulsive disorder is a worldwide psychiatric disorder with alifetime prevalence of 2% and mainly characterized by obsessional ideasand compulsive behaviors and rituals. Bilateral stimulation in theanterior limbs of the internal capsules (Nuttin, Cosyns et al., 1999;Nuttin, Gabriels et al., 2003) or nucleus accumbens stimulation (Sturm,Lenartz et al., 2003) can improve symptoms but at high frequency andhigh intensity stimulation. Thus, embodiments herein can be used toproduce burst mode stimulation to treat an obsessive-compulsivedisorder. 3. Tourette's Syndrome

Tourette syndrome (TS) is a neuropsychiatric disorder with onset inearly childhood. It is characterized by tics and often accompanied bydisturbances in behavior, such as obsessive-compulsive disorder (OCD).Bilateral thalamic stimulation, with promising results on tics andobsessive-compulsive symptoms has been performed as a treatment.(Visser-Vandewalle, Temel et al., 2003; Temel and Visser-Vandewalle2004). Thus, it is envisioned that the stimulation system and/or methodof embodiments herein can be used to treat TS.

One or more of the operations described above in connection with themethods may be performed using one or more processors. The differentdevices in the systems described herein may represent one or moreprocessors, and two or more of these devices may include at least one ofthe same processors. In one embodiment, the operations described hereinmay represent actions performed when one or more processors (e.g., ofthe devices described herein) execute program instructions stored inmemory (for example, software stored on a tangible and non-transitorycomputer readable storage medium, such as a computer hard drive, ROM,RAM, or the like).

The processor(s) may execute a set of instructions that are stored inone or more storage elements, in order to process data. The storageelements may also store data or other information as desired or needed.The storage element may be in the form of an information source or aphysical memory element within the controllers and the controllerdevice. The set of instructions may include various commands thatinstruct the controllers and the controller device to perform specificoperations such as the methods and processes of the various embodimentsof the subject matter described herein. The set of instructions may bein the form of a software program. The software may be in various formssuch as system software or application software. Further, the softwaremay be in the form of a collection of separate programs or modules, aprogram module within a larger program or a portion of a program module.The software also may include modular programming in the form ofobject-oriented programming. The processing of input data by theprocessing machine may be in response to user commands, or in responseto results of previous processing, or in response to a request made byanother processing machine.

The controller may include any processor-based or microprocessor-basedsystem including systems using microcontrollers, reduced instruction setcomputers (RISC), application specific integrated circuits (ASICs),field-programmable gate arrays (FPGAs), logic circuits, and any othercircuit or processor capable of executing the functions describedherein. When processor-based, the controller executes programinstructions stored in memory to perform the corresponding operations.Additionally or alternatively, the controllers and the controller devicemay represent circuits that may be implemented as hardware. The aboveexamples are exemplary only, and are thus not intended to limit in anyway the definition and/or meaning of the term “controller.”

It is to be understood that the subject matter described herein is notlimited in its application to the details of construction and thearrangement of components set forth in the description herein orillustrated in the drawings hereof. The subject matter described hereinis capable of other embodiments and of being practiced or of beingcarried out in various ways. Also, it is to be understood that thephraseology and terminology used herein is for the purpose ofdescription and should not be regarded as limiting. The use of“including,” “comprising,” or “having” and variations thereof herein ismeant to encompass the items listed thereafter and equivalents thereofas well as additional items.

It is to be understood that the above description is intended to beillustrative, and not restrictive. For example, the above-describedembodiments (and/or aspects thereof) may be used in combination witheach other. In addition, many modifications may be made to adapt aparticular situation or material to the teachings of the inventionwithout departing from its scope. While the dimensions, types ofmaterials and coatings described herein are intended to define theparameters of the invention, they are by no means limiting and areexemplary embodiments. Many other embodiments will be apparent to thoseof skill in the art upon reviewing the above description. The scope ofthe invention should, therefore, be determined with reference to theappended claims, along with the full scope of equivalents to which suchclaims are entitled. In the appended claims, the terms “including” and“in which” are used as the plain-English equivalents of the respectiveterms “comprising” and “wherein.” Moreover, in the following claims, theterms “first,” “second,” and “third,” etc. are used merely as labels,and are not intended to impose numerical requirements on their objects.Further, the limitations of the following claims are not written inmeans—plus-function format and are not intended to be interpreted basedon 45 U.S.C. § 112(f), unless and until such claim limitations expresslyuse the phrase “means for” followed by a statement of function void offurther structure.

What is claimed is:
 1. A method to deliver nested stimulation to nervetissue of interest, the method comprising: setting first parameters thatdefine a carrier waveform; setting second parameters that define a highfrequency waveform, wherein at least one of the carrier waveform andhigh frequency waveform are defined to correspond to physiologic neuraloscillations associated with the nerve tissue of interest; operating apulse generator to generate a nested stimulation waveform that combinesthe carrier waveform and high frequency waveform, the nested stimulationwaveform having a plurality of pulse bursts; and delivering the nestedstimulation waveform through one or more electrodes to the nerve tissueof interest.
 2. The method of claim 1, wherein the nerve tissue ofinterest includes brain tissue of interest, and wherein the highfrequency waveform corresponding to high-frequency physiologic neuraloscillations associated with brain tissue of interest, and herein thepulse bursts including pulses having a frequency corresponding to thehigh frequency neural oscillations.
 3. The method of claim 1, whereinthe carrier waveform corresponds to low-frequency physiologic neuraloscillations associated with the nerve tissue of interest.
 4. The methodof claim 3, wherein the pulse bursts are separated from one another witha burst to burst period that corresponds to a frequency of thelow-frequency neural oscillations.
 5. The method of claim 1, wherein thefirst and second parameters define at least one of an amplitude, burstto burst frequency, pulse frequency, pulse width, burst length and burstperiod for the plurality of pulse bursts.
 6. The method of claim 1,further comprising combining the carrier and high-frequency waveformsutilizing one of the following types of cross frequency coupling: powerto power; phase to power; phase to phase; phase to frequency; power tofrequency and frequency to frequency.
 7. The method of claim 1, whereinthe carrier and high-frequency waveforms are combined through phase topower cross frequency coupling, in which the phase of the carrierwaveform modulates the power of the high-frequency waveform.
 8. Themethod of claim 1, wherein the first parameters are set to define thecarrier waveform to correspond to the theta wave frequency band, whilethe second parameters are set to define the high-frequency waveform tocorrespond to the gamma wave frequency band, the method furthercomprising managing the nested stimulation waveform modulating theneural oscillations in the gamma wave frequency band in connection withat least one of sensory, motor, and cognitive events.
 9. The method ofclaim 1, wherein the nerve tissue of interest includes brain tissue ofinterest, and further comprising managing the nested stimulationwaveform in connection with an event of interest through cross frequencycoupling between theta and gamma waves associated with brain tissue ofinterest.
 10. The method of claim 1, wherein the nerve tissue ofinterest includes brain tissue of interest, and wherein the brain tissueof interest comprises distributed neural modules located in separateregions of the brain, the method further comprising managing the nestedstimulation waveform in connection with cross frequency coupling betweenneural oscillations associated with the distributed neural modules thatexhibit long-distance communication over neural oscillations within atleast one of delta, theta and alpha wave frequency bands.
 11. The methodof claim 1, further comprising measuring intrinsic neural oscillations,determining whether the nested stimulation waveform is achievingentrainment of the intrinsic neural oscillations, and adjusting at leastone of the first and second parameters to maintain entrainment of theintrinsic neural oscillations.
 12. A system to deliver nestedstimulation to nerve tissue of interest, the system comprising: a leadhaving an array of stimulation electrodes, the lead configured to beimplanted at a target position proximate to nerve tissue of interest;and an implantable medical device (IMD) coupled to the lead, the IMDincluding a processor and memory storing programmable instructions, theprocessor executing the programmable instructions to: set firstparameters that define a carrier waveform; set second parameters thatdefine a high frequency waveform, wherein at least one of the carrierwaveform and high frequency waveform are defined to correspond tophysiologic neural oscillations associated with the nerve tissue ofinterest; operate a pulse generator to generate a nested stimulationwaveform that combines the carrier waveform and high frequency waveform,the nested stimulation waveform having a plurality of pulse bursts; anddeliver the nested stimulation waveform through one or more electrodesto the nerve tissue of interest.
 13. The system of claim 12, wherein thehigh frequency waveform corresponding to high-frequency physiologicneural oscillations associated with the nerve tissue of interest, andherein the pulse bursts including pulses having a frequencycorresponding to the high frequency physiologic neural oscillations. 14.The system of claim 12, wherein the carrier waveform corresponds tolow-frequency physiologic neural oscillations associated nerve tissue ofinterest.
 15. The system of claim 14, wherein the pulse bursts areseparated from one another with a burst to burst period that correspondsto a frequency of the low-frequency neural oscillations.
 16. The systemof claim 12, wherein the first and second parameters define at least oneof an amplitude, burst to burst frequency, pulse frequency, pulse width,burst length and burst period for the plurality of pulse bursts.
 17. Thesystem of claim 12, wherein the processor combines the carrier andhigh-frequency waveforms utilizing one of the following types of crossfrequency coupling: power to power, phase to power; phase to phase;phase to frequency; power to frequency and frequency to frequency. 18.The system of claim 12, wherein the processor combines the carrier andhigh-frequency waveforms through phase to power cross frequencycoupling, in which the phase of the carrier waveform modulates the powerof the high-frequency waveform.
 19. The system of claim 12, wherein thenerve tissue of interest includes at least one of brain tissue, spinalcord tissue and dorsal root ganglion tissue.
 20. The system of claim 12,wherein the lead includes sensing electrodes, and the processor:measures intrinsic neural oscillations through the sensing electrodes;determines whether the nested stimulation waveform is achievingentrainment of the intrinsic neural oscillations; and adjusts at leastone of the first and second parameters to maintain entrainment of theintrinsic neural oscillations.